Physiol Rev 95: 405–511, 2015
doi:10.1152/physrev.00042.2012
RENAL AUTOREGULATION IN HEALTH AND DISEASE
Mattias Carlström, Christopher S. Wilcox, and William J. Arendshorst
Department of Medicine, Division of Nephrology and Hypertension and Hypertension, Kidney and Vascular Research
Center, Georgetown University, Washington, District of Columbia; Department of Physiology and Pharmacology,
Karolinska Institutet, Stockholm, Sweden; and Department of Cell Biology and Physiology, UNC Kidney Center,
and McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
Carlström M, Wilcox CS, Arendshorst WJ. Renal Autoregulation in Health and Disease. Physiol Rev 95: 405–511, 2015; doi:10.1152/physrev.00042.2012.—Intrarenal autoregulatory mechanisms maintain renal blood flow (RBF) and glomerular filtration
rate (GFR) independent of renal perfusion pressure (RPP) over a defined range (80 –180
mmHg). Such autoregulation is mediated largely by the myogenic and the macula densatubuloglomerular feedback (MD-TGF) responses that regulate preglomerular vasomotor tone primarily
of the afferent arteriole. Differences in response times allow separation of these mechanisms in the
time and frequency domains. Mechanotransduction initiating the myogenic response requires a sensing mechanism activated by stretch of vascular smooth muscle cells (VSMCs) and coupled to intracellular signaling pathways eliciting plasma membrane depolarization and a rise in cytosolic free calcium
concentration ([Ca2⫹]i). Proposed mechanosensors include epithelial sodium channels (ENaC), integrins, and/or transient receptor potential (TRP) channels. Increased [Ca2⫹]i occurs predominantly by
Ca2⫹ influx through L-type voltage-operated Ca2⫹ channels (VOCC). Increased [Ca2⫹]i activates inositol
trisphosphate receptors (IP3R) and ryanodine receptors (RyR) to mobilize Ca2⫹ from sarcoplasmic
reticular stores. Myogenic vasoconstriction is sustained by increased Ca2⫹ sensitivity, mediated by
protein kinase C and Rho/Rho-kinase that favors a positive balance between myosin light-chain kinase
and phosphatase. Increased RPP activates MD-TGF by transducing a signal of epithelial MD salt
reabsorption to adjust afferent arteriolar vasoconstriction. A combination of vascular and tubular
mechanisms, novel to the kidney, provides for high autoregulatory efficiency that maintains RBF and
GFR, stabilizes sodium excretion, and buffers transmission of RPP to sensitive glomerular capillaries,
thereby protecting against hypertensive barotrauma. A unique aspect of the myogenic response in the
renal vasculature is modulation of its strength and speed by the MD-TGF and by a connecting tubule
glomerular feedback (CT-GF) mechanism. Reactive oxygen species and nitric oxide are modulators of
myogenic and MD-TGF mechanisms. Attenuated renal autoregulation contributes to renal damage in
many, but not all, models of renal, diabetic, and hypertensive diseases. This review provides a summary
of our current knowledge regarding underlying mechanisms enabling renal autoregulation in health and
disease and methods used for its study.
L
I.
II.
III.
IV.
V.
VI.
VII.
VIII.
INTRODUCTION
MAJOR MECHANISMS AND METHODS ...
MECHANOSENSITIVE MECHANISM...
CONDUCTANCE CHANGES...
CALCIUM SIGNALING PATHWAYS...
MODULATING AGENTS
RENAL AUTOREGULATION IN DISEASE...
CONCLUSIONS
405
408
431
436
439
444
452
471
I. INTRODUCTION
A. Overview and Historical Perspective
Arteries from various vascular beds often share functional
characteristics. However, prominent differences exist in myogenic responses to changes in transmural pressure. These responses are greater in cerebral and renal than in mesenteric
and hindlimb arteries (748, 750, 859, 886). Vascular smooth
muscle cells (VSMCs) are derived from diverse embryological
and developmental origins, and such lineage may account for
heterogeneity of specialized function (1142, 1179). Renal vessels are formed by angiogenesis and vasculogenesis (479).
VSMCs express fast and slow contractile gene programs, accounting for phasic and tonic phenotypes (1213). The aorta
and efferent arterioles are examples of the tonic phenotype,
whereas small resistance arteries and arterioles including the
renal cortical radial (interlobular) artery and afferent arteriole
are examples of the phasic phenotype. Moreover, there are
significant differences in the magnitude of vasoconstrictor responses to KCl, norepinephrine (NE), and serotonin and to
endothelium-dependent and -independent vasodilation between mouse aorta and smaller arterial segments (804).
These variations likely reflect, in part, functional adaptations to meet the diverse roles of different arterial beds.
0031-9333/15 Copyright © 2015 the American Physiological Society
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RENAL AUTOREGULATORY MECHANISMS
Cerebral artery tone is modulated primarily by local metabolic, paracrine, and mechanical factors such as the partial
pressure of carbon dioxide. The cerebral vasculature adjusts blood flow to the local metabolic demand independent
of systemic hemodynamics. The cerebral vascular myogenic
response mediates rapid and efficient autoregulation of cerebral blood flow that maintains a steady cerebral capillary
pressure (356, 739). In contrast, mesenteric arteries are
strongly influenced by transmitter release from perivascular
sympathetic nerves. They have a major role in the control of
peripheral vascular resistance and arterial blood pressure
(BP) (410). In the splanchnic circulation, the portal vein and
hepatic artery are arranged in parallel and supply blood to
the liver for detoxification and metabolism. The specialized
pulmonary circulation is characterized by its low vascular
pressure and resistance and inherent vasoconstrictor response to hypoxia. These organ-specific regulatory actions
interact with myogenic vasoconstriction.
Semple and DeWardener (1347) quantified the efficiency of
autoregulation by an “autoregulatory index” (AI) defined
as the steady-state change in RBF factored by the sustained
change in mean RPP (1347). An AI of zero indicates perfect
autoregulation, whereas an AI close to 1.0 or above signifies
very ineffective RBF autoregulation. Low AI values (⬍0.2),
reflecting effective steady-state RBF autoregulation, have
been reported in the kidneys of anesthetized dogs (90, 269,
745, 763, 799, 953, 954, 1295, 1344, 1531), mice (583,
751, 756, 1360), rabbits (80, 385, 902, 1141, 1270, 1623),
and rats (41, 45, 46, 269, 422, 709, 790, 833, 1105, 1131,
1188, 1270) as well as in conscious rats (270, 423, 668,
1195, 1376) and dogs (69, 97, 421, 510, 511, 753–755,
760, 799, 1172, 1172–1174, 1263, 1618) in both short and
prolonged settings (42, 1241). Autoregulation in the kidneys of conscious dogs and anesthetized rats is considerably
more complete than in the mesenteric or hindlimb vascular
beds (602, 750).
The kidney is richly perfused and renal blood flow (RBF)
normally accounts for ⬃25% of cardiac output. Autoregulation is a fundamental component of renal function. It
integrates intrinsic intrarenal mechanisms that stabilize
RBF and glomerular filtration rate (GFR) during changes in
renal perfusion pressure (RPP) over a defined range. This
requires that the renal vascular resistance (RVR) changes in
proportion to the RPP. The cortical radial arteries, and
especially the afferent arterioles, are the major preglomerular resistance vessels whose tone mediates most of pressureinduced autoregulation of RBF and GFR. The efferent arterioles usually do not participate in RBF autoregulation,
although they may contribute to autoregulation of GFR at
low RPP under certain conditions such as low-salt diet and
activation of the renin-angiotensin system (RAS) with high
angiotensin II (ANG II) levels. Renal autoregulation is
achieved primarily by a unique orchestrated action of two
major mechanisms: the myogenic response and the macula
densa tubuloglomerular feedback (MD-TGF) response. Together they adjust the tone of the preglomerular VSMCs to
buffer the challenge of a constantly changing RPP, whether
spontaneous or induced. The fast myogenic response relates
the tone of the afferent arterioles to their intraluminal pressure by intrinsic adjustments in the tension of VSMCs. The
more delayed MD-TGF response is activated by tubular
electrolyte delivery and reabsorption primarily by a luminal
Na⫹/K⫹/2Cl⫺ type 2 (NKCC2) cotransporter and a
Na⫹/H⫹ exchanger on the MD cells at the end of the thick
ascending limb (TAL) of Henle’s loop to elaborate positive
and negative modulators of vasoconstriction of the adjacent
afferent arteriole. The ensuing collective response entails
extensive, bidirectional, and time-dependent interactions
between these two mechanisms. Renal autoregulation is
intrinsic to the kidney and thus largely independent of extrinsic nerves or circulating hormones (428, 998, 1053,
1344, 1345, 1360, 1465, 1578).
The myogenic phenomenon was first described for large
conduit arteries by Bayliss et al. (76) more than a century
ago as part of his investigation of reactive hyperemia in the
kidney. Renal autoregulation to acute changes in RPP was
characterized originally in rabbits by Forster and Maes in
1947 (428) and in dogs by Selkurt et al. in 1949 (1345). The
renal myogenic response was initially described by Gilmore
et al. (473) in 1980 in hamster preglomerular arterioles. The
unique renal MD-TGF occurs within the juxtaglomerular
apparatus (JGA) that is composed of the MD cells at the
junction of the TAL of the loop of Henle and the distal
tubule, the granular renin-containing cells in the distal afferent arteriole and the extraglomerular mesangium that is
interspersed between, or surrounds, these cells. The anatomy of different cell types in the JGA is shown in FIGURE 1.
The concept of the JGA coordinating tubular and glomerular functions was introduced originally by Goormaghtigh
in 1937 (487), with subsequent hypotheses by Guyton,
Harsing, and Thurau in the early 1960s (533, 581, 1465,
1466). The specific contribution of MD-TGF to renal autoregulation of GFR was demonstrated initially by the laboratories of Navar and Schnermann in the 1970s (1022,
1064, 1070, 1190, 1191, 1317).
406
A myogenic response is observed in the renal, cerebral, coronary, pulmonary, mesenteric, and skeletal muscle vasculature (300 –302, 703, 739, 1249). This response limits vascular wall strain by reciprocal adjustments in vessel radius
during changes in the transmural pressure gradient. This
assumes that the wall thickness remains the same, as described by the LaPlace relationship. Mechanotransduction
in VSMCs to increased PP is intrinsic to VSMC and entails
stretch or distortion of the plasma membrane coupled to
mechanisms that decrease membrane conductance, thereby
depolarizing the resting membrane potential (EM) from approximately ⫺40 mV to activate voltage-operated Ca2⫹
channels (VOCCs). The ensuing increase in Ca2⫹ entry el-
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CARLSTRÖM ET AL.
PSF
Grease
block
Efferent
arteriole
Glomerulus
PGC
Granular renincontaining cells
Afferent
arteriole
Blood
Connecting
tubule
Extraglomerular
mesangial cells
Macula
densa
cells
Distal
tubule
Proximal
convoluted
tubule
Thick
ascending
limb
FIGURE 1. Schematic diagram illustrating the anatomy of the juxtaglomerular apparatus (JGA) showing cell
types involved in renal autoregulation, i.e., myogenic response and macula densa (MD)-mediated tubuloglomerular feedback (MD-TGF). MD cells are located at the junction of the thick ascending limb of Henle’s loop and
the distal convoluted tubule. Their basolateral membrane contacts some extraglomerular mesangial cells,
which in turn are contiguous with vascular smooth muscle cells and renin-containing juxtaglomerular granular
cells at the end of the afferent arteriole. Endothelial nitric oxide synthase (eNOS) is expressed primarily in the
endothelium of the afferent arteriole and neuronal NOS (nNOS) in the MD cells. MD-TGF can be assessed
conveniently by measuring proximal stop-flow pressure (PSF) upstream of a grease block in the nephron as an
index of glomerular capillary pressure (PGC) during variations in fluid delivery to MD cells by perfusion from
another micropipette (not shown) placed downstream from the block. Recent in vitro and in vivo PSF measurements have demonstrated functional implications of a connecting tubule glomerular feedback (CT-GF) in
regulating afferent arteriolar vasomotor tone.
evates cytosolic Ca2⫹ concentration ([Ca2⫹]i) that subsequently mobilizes Ca2⫹ stored in the sarcoplasmic reticulum (a process termed Ca2⫹-induced Ca2⫹ release, CICR),
combined with signaling pathways that enhance the sensitivity of myosin to a given [Ca2⫹]i (i.e., Ca2⫹ sensitivity).
These coordinated actions activate myosin light chain kinase (MLCK) and/or inhibit myosin light chain phosphatase (MLCP) to promote contraction of VSMCs (1328,
1392). This sequence of events is summarized in FIGURE 8.
The relative importance of Ca2⫹ influx, release, and sensitization varies considerably among published studies.
The MD-TGF is sensitive to renal metabolism. It relates the
GFR to the NaCl delivery to and reabsorption by MD cells.
MD NaCl delivery, in turn, is related to the filtered load of
NaCl and reabsorption in nephron segments upstream of
the MD, all of which therefore can affect MD-TGF. Accordingly, MD-TGF integrates tubular and vascular function
and is thus a unique renal mechanism of autoregulation.
Activated MD cells generate signaling molecule(s) such as
ATP and/or its breakdown product adenosine that traverse
the interstitial space and extraglomerular mesangial cells,
likely involving connexins (Cxs), to stimulate Ca2⫹ signaling and contract the afferent arteriole. The ATP and aden-
osine responses are primarily mediated by purinergic P2X
receptors and adenosine A1 receptors, respectively, on
VSMC and possibly mesangial cells.
Mesangial cells may contribute to MD-TGF by providing
an extraglomerular conduit pathway, but these cells lack
the expression of contractile ␣-smooth muscle actin in vivo
that is present in vitro in cell culture, and therefore probably
are not contractile in life (341, 378, 796). Because of difficulty in isolating fresh mesangial cells from glomeruli, they
are usually studied in culture to obtain a homogeneous
population (3, 607, 1615). However, it is recognized that
phenotypic changes take place as a function of passage
number, for example, in the relative amounts of contractile
proteins. VSMC in culture can undergo phenotypic switching from a nondividing contractile phenotype to a proliferative dedifferentiated phenotype characterized by reduced
mRNA and protein levels of VSMC markers (1142). Thus
results for contraction mechanisms using cultured mesangial cells should be interpreted with caution.
Although the general operation of MD-TGF in renal autoregulation is appreciated, the understanding of its fine details is still evolving. It is generally accepted that an increase
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RENAL AUTOREGULATORY MECHANISMS
in RPP initially increases single-nephron glomerular filtration rate (SNGFR) and might reduce proximal tubule reabsorption, thereby increasing NaCl delivery from Henle’s
loop to the MD (FIGURE 1). Increased NaCl reabsorption by
MD cells generates a signal that mediates contraction of the
afferent arteriole. Thus MD-TGF functions as a negativefeedback circuit that increases preglomerular vascular resistance to restrain single-nephron glomerular blood flow
(SNGBF) and glomerular capillary hydraulic pressure
(PGC), thereby stabilizing GFR and RBF during changes in
RPP. The MD-TGF system is sensitive to factors that regulate tubular reabsorption. Therefore, MD-TGF relates renal
autoregulation to extracellular fluid volume (ECV) homeostasis. MD-TGF is sensitive to tubular metabolism because
it couples epithelial cell salt transport to preglomerular vascular tone utilizing metabolic intermediates such as ATP
and adenosine as well as other tubular and vascular metabolites or signaling molecules such as nitric oxide (NO), superoxide anion (O2⫺), prostaglandin endoperoxide (PGH2),
thromboxane A2 (TxA2), carbon monoxide (CO), and
prostaglandin E2 (PGE2) (FIGURE 6). Ultimately, both myogenic and MD-TGF mechanisms impact regulation of RBF
and GFR, primarily by varying the degree of afferent arteriolar vasoconstriction (51, 703, 1436). Their individual
contributions, as well as their interactions, determine the
overall autoregulatory efficacy.
This review focuses on mechanisms responsible for renal
autoregulation in health and its role and regulation in several models of hypertension, chronic kidney disease (CKD)
and diabetes mellitus (DM). GFR normally is autoregulated
with RBF since both respond in parallel to induced changes
in preglomerular resistance. However, GFR is determined
not only by PGC but also by SNGBF and by the capillary
ultrafiltration coefficient (KUF). Selective changes in efferent
arteriolar resistance, for example, during inhibition of the
RAS at low RPP, can dissociate autoregulation of GFR from
RBF (550, 1261). This review concentrates on the changes
in preglomerular vascular resistance responsible for regulation of RBF and glomerular perfusion. The reader is referred to recent reviews of renal autoregulation (286, 748,
933, 934) and of mathematical modeling of renal autoregulatory mechanisms (179, 228, 395, 541, 628, 805, 877,
973, 1023, 1350, 1614).
B. Functional Significance
Renal autoregulation subserves four important functions.
First, it sets a basal level of vasomotor tone upon which
neurohumoral agents, paracrine/autocrine substances, and
metabolic factors adjust RVR (48, 1065, 1071). Second, it
buffers the transmission of RPP to the sensitive glomerular
capillaries and parenchyma, thereby preventing intrarenal
barotrauma during systemic arterial hypertension (108).
Impaired renal autoregulation contributes to progressive
pressure-sensitive glomerular and interstitial injury in many
408
models of hypertension, CKD, and DM as described in
detail in section VII. Third, it isolates the subtle tubular
transport processes and sodium (Na⫹) excretion from
abrupt changes in GFR that would induce large fluctuations
in tubular fluid flow and peritubular physical forces (532).
Fourth, a somewhat less complete regulation of medullary
blood flow during changes in RPP has been proposed as a
mechanism mediating pressure-natriuresis and may be important in maintaining salt and water balance and controlling BP, as discussed in section IIA2.
Unfortunately, there are only limited studies of renal autoregulation in normal human subjects or those with hypertension. A study of African-American hypertensive patients
reported higher values for GFR and RBF than matched
Caucasians (FIGURE 2, A–C) (826). A pressor infusion of NE
increased the GFR only in the African-Americans, which led
the authors to propose that African-American hypertensives had impaired renal autoregulation, although the RBF
was maintained independent of RPP in both groups. In
another study of hypertensive patients, the systolic BP was
reduced incrementally by infusion of the vasodilator sodium nitroprusside (FIGURE 2, D AND E) that releases NO
(20). The GFR and effective renal plasma flow were wellmaintained across the range of systolic BPs of 170 to 130
mmHg in patients with moderate hypertension, but both
fell progressively in the range of 200 –135 mmHg in those
with severe hypertension. This demonstrated preservation
of renal autoregulation in patients with moderate hypertension, but a breakdown in autoregulation in those with severe hypertension. Thus renal autoregulation can provide a
remarkably stable GFR and RBF during changes in RPP in
human subjects with hypertension. The observation of impaired autoregulation in hypertensive African-Americans
and those with severe hypertension is consistent with the
hypothesis that renal autoregulation normally functions to
protect the kidney from barotrauma. Its failure in these two
populations increases risk for the development of nephrosclerosis and hypertensive CKD.
II. MAJOR MECHANISMS AND METHODS
USED TO STUDY RENAL
AUTOREGULATION
Autoregulation has been characterized in different preparations of the renal circulation ranging from in vivo
measurements of RPP-induced changes in whole kidney
RBF, GFR, and single-nephron hemodynamics during induced changes in RPP to direct assessment of pressureinduced contraction of isolated, perfused afferent arterioles, or flow-induced MD-TGF responses in isolated
JGAs. Examples of autoregulatory myogenic responses
from six commonly used preparations are described below and are highlighted in FIGURE 3, A–F.
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CARLSTRÖM ET AL.
160
150
*
140
130
White Black
ERBF
1,500
**
1,400
1,300
1,200
1,100
1,000
900
C
GFR
200
P<0.001
180
160
140
*
120
100
White Black
White Black
D
GFR
150
130
110
90
70
**
50
130 140 150 160 170 180 190 200
E
CHipurran (ml · min-1 ·1.73 m-2)
P<0.001
B
CCr (ml · min-1 ·1.73 m-2)
SBP (mmHg)
170
P<0.001
GFR (ml · min-1 ·1.73 m-2)
BP
180
ERBF (ml · min-1 ·1.73 m-2)
A
ERPF
450
400
350
300
250
**
200
150
130 140 150 160 170 180 190 200
FIGURE 2. Studies of renal autoregulation in hypertensive human subjects. Blood pressure (BP) was
determined at regular intervals, and the glomerular filtration rate (GFR) was measured from the clearance of
inulin or creatinine and the effective renal plasma flow (ERPF) from the clearance of hippuran and used to
calculate the effective renal blood flow (ERBF). A–C: data were compared in 33 Caucasian (white) and 29
African-Americans (black) matched patients with essential hypertension in the basal state (open boxes) and
during infusion of norepinephrine (0.05 ␮g·kg⫺1·min⫺1 for 30 min) to increase BP (closed boxes). The ERBF
was higher in African-American than in Caucasian subjects but did not change during a short-term elevation of
BP by norepinephrine in either patient group. However, the GFR also was higher in the African-Americans and
increased further with the rise in BP, implying a selective defect in GFR autoregulation. Compared with
Caucasians in the basal state: *P ⬍ 0.05; **P ⬍ 0.01. [Data from Kotchen et al. (826).] D and E: data were
compared in patients with moderate hypertension (average: 170/108 mmHg; n ⫽ 10, open circles) and
severe hypertension (average: 198/127 mmHg; n ⫽ 10; closed circles), in the basal state and during graded
infusion of sodium nitroprusside (0.2–12 ␮g·kg⫺1·min⫺1) to provide incremental reductions in systolic BP
(SBP). After acute BP normalization, the GFR and the ERPF were reduced significantly in patients with severe
hypertension (⫺44.7 ⫾ 6.8 and ⫺41.6 ⫾ 8.3%, respectively), but did not change in those with moderate
hypertension, implying that renal autoregulation was preserved in subjects with essential hypertension, but was
impaired or absent in those with severe hypertension. **P ⬍ 0.01 vs. recordings in the basal state with high
BP. [Data from Almeida et al. (20).]
A. In Vivo Studies Using Whole Kidney
Preparations
1. Steady-state autoregulation
A) STEADY-STATE AUTOREGULATION OF WHOLE KIDNEY BLOOD
FLOW.
The BP in animal studies can be increased by carotid
arterial occlusion to elicit baroreceptor activation of the
sympathetic nervous system. Graded reductions of the elevated RPP by constriction of the suprarenal aorta for 1–2
min can provide a range of RPPs above, at, and below the
ambient RPP (FIGURE 3A) (41, 46). Ideally, this should be
achieved by coupling an aortic or renal artery constrictor to
a servo-controlled pressure sensor to provide more stable
levels of RPP (46, 376, 549, 610). The kidneys should be
denervated to minimize the influence of changes in renal
sympathetic nerve activity. Alternatively, the RPP can be
increased by constriction of the abdominal aorta below the
renal vessels. This can be combined with occlusion of the
superior mesenteric and celiac arteries to increase the RPP,
with a further rise in PP achieved by infusion of a cocktail of
vasoconstrictors such as NE and arginine vasopressin
(AVP) (1247). A limitation of this method is that the infused
hormones themselves affect renal vascular tone and may
modulate autoregulation. Another approach has been to
study an isolated, pump-perfused kidney of dogs (1106,
1108, 1110, 1112, 1120) or rats (1285, 1323). The oxygenated perfusate usually contains albumin or a colloid, but
has a low hematocrit to minimize erythrocyte damage by
the perfusion pump. The reduced red cell mass limits the
vessel wall shear stress and NO release, but this is offset by
some degree by less oxyhemoglobin-mediated oxidation of
NO, whose influence may thereby become more pronounced. Perfusion is usually at a fixed mean RPP rather
than a pulsatile pressure. Limitations are that the isolated
kidneys become edematous, fail to reabsorb salt normally,
and have limited autoregulatory efficiency (870, 871, 1332,
1468).
B) STEADY-STATE AUTOREGULATION IN DIFFERENT REGIONS OF THE
KIDNEY. Most current studies of renal cortical blood flow use
a fiberoptic probe connected to a laser Doppler flowmeter
to estimate the erythrocyte (RBC) velocity in a small tissue
area (⬃1 mm3). Highly efficient autoregulation was reported in the outer-, mid- and deep-cortical regions of rat
kidneys during hydropenia (990, 1195, 1248, 1252) and
during acute expansion of ECV (990, 1248). Autoregulation of cortical blood flow generally parallels that of the
whole kidney.
Measurement of medullary blood flow is considerably more
complex (283, 1256, 1423). For example, measurements of
average RBC velocity by Doppler methods applied to the
medulla do not differentiate between descending and ascending flow in vasa recta capillaries. Volume flux depends
on the number of vessels being perfused and the fluid reabsorbed by the tubules. This may explain in part why the
efficiency of medullary autoregulation has been more vari-
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RENAL AUTOREGULATORY MECHANISMS
able among studies and species and in some depends on the
state of hydration.
Both cortical and medullary blood flow in nondiuretic rats
are autoregulated efficiently between RPP of 90 –160
mmHg (267, 288, 990, 1248, 1417).
An early study that measured the RBC velocity in individual
vessels on the surface of the renal papilla reported excellent
autoregulation during hydropenia and volume expansion
(267). However, other studies using similar methodology
110
RBF (% basal)
100
Rat dynamic autoregulation: time domain
RVR
(mmHg)
B
Rat steady state autoregulation
120
RVR
(% of perfect AR)
A
reported weak autoregulation of RBC velocity in descending and ascending vasa recta of euvolemic rats, with AI
values of 0.5– 0.8 (391). Many subsequent studies in rats
that have used the laser Doppler technique to measure RBC
velocity in multiple capillaries in a fixed volume of tissue
reported highly efficient autoregulation of blood flow in the
outer and inner portions of the renal medulla in hydropenia
(990), but this became substantially less efficient during
ECV expansion (277, 411, 717, 990, 1243, 1251, 1252,
1254, 1257, 1476). However, another study reported only
moderate medullary autoregulation (AI ⫽ 0.4) in hydro-
100
105
AI < 0.1
90
80
70
AI < 0.05
60
50
40
45
55
65
75
85
95
50
TGF: ~35% of total
0
MR: ~50% of total
-50
0
105 115 125 135 145
60
80
100
120
Time after release (sec)
Rat dynamic autoregulation: frequency domain
D
Rat juxtamedullary preparation
140
2.0
AI = 0.32
MR - 65%
CCB
120
Diameter
(% of control)
Admittance gain
40
20
Renal PP (mmHg)
C
3rd
90
1.0
TGF - 35%
0.5
MR - 65%
100
TGF block
TGF - 35%
80
Control
60
0.25
0.01
0.1
1
60
E
100
80
120
140
Renal PP (mmHg)
Frequency (Hz)
Rat hydronephrotic kidney
F
Mouse isolated perfused afferent arteriole
0
-5
Active wall tensions
(dynes/cm)
Afferent arteriolar diameter
(% change)
400
-10
-15
-20
300
200
100
-25
0
80
100
120
140
160
Renal PP (mmHg)
410
180
40
60
80
100
Arteriolar PP (mmHg)
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140
CARLSTRÖM ET AL.
penic rats with little change (AI ⫽ 0.5) during ECV expansion (1248). An important study concluded that ECV expansion increases renal medullary blood flow by increasing
the number of capillaries perfused with moving RBCs without a change in their velocity in either ascending or descending vasa recta (415). Further evidence of incomplete medullary blood flow autoregulation came from the observation that the hydrostatic pressure in the vasa recta
capillaries was autoregulated less completely than in the
cortical peritubular capillaries (1248).
The renal medulla is perfused from cortical efferent arterioles. Therefore, the finding that medullary perfusion in the
rat can be poorly autoregulated, especially during ECV expansion, while deep cortical blood flow is well autoregulated located the postglomerular vasculature as the site of
impaired control of medullary blood flow (990).
Highly efficient autoregulation of both cortical and medullary blood flow that is independent of the ECV is observed
in whole kidney studies in the dog (950, 951, 954, 960, 961)
and in the rabbit (381). On the other hand, one study reports that blood flow to the exposed papilla of the dog was
poorly autoregulated (AI ⫽ 0.82) compared with whole
kidney RBF (AI ⫽ 0.33) (1423), but this may have been a
consequence of the impaired function of the exposed papilla.
In summary, in contrast to cortical blood flow, the degree of
autoregulation of medullary blood flow in the rat is controversial. Although most studies have reported efficient autoregulation of medullary blood flow during hydropenia, this
appears to become less efficient during ECV expansion, at
least in the rat (277, 990, 1243, 1251, 1252, 1254, 1257).
However, most studies in dogs and rabbits report efficient
medullary autoregulation during both hydropenia and ECV
expansion. Autoregulatory responses of the preglomerular
vasculature can be assessed directly in the in vitro rat juxtamedullary nephrovascular (JMN) preparation. As discussed in section IIB3, these studies generally have reported
efficient autoregulation, involving both myogenic and MDTGF components.
2. Pressure-natriuresis
The reports of highly efficient overall renal autoregulation,
and often also of intrarenal distribution of perfusion in the
dog, rabbit, and nondiuretic rat, pose a conundrum for the
understanding of how the kidney regulates NaCl and fluid
excretion to maintain long-term BP homeostasis. Renal
Na⫹ excretion changes acutely with RPP, even in studies in
which the intrarenal mechanisms maintain a stable blood
flow in the renal cortex and medulla. Further uncertainty
derives from the recognition that steady-state measurements of proximal reabsorption and peritubular capillary
fluid uptake do not permit firm conclusions regarding causality (1490). Thus the rate of reabsorption must correlate
with the effective reabsorptive pressure determined by Starling physical forces and the peritubular capillary reabsorptive coefficient. Moreover, the events that initiate the response may be transient yet the GFR and the filtered Na⫹
load remain constant during changes in PP. This indicates
that the changes in Na⫹ excretion must be due to variations
in tubular Na⫹ reabsorption. The key question is: What
intrarenal mechanism(s) can mediate pressure-natriuresis
when the pressures in the tubules and vasculature downstream of the afferent arteriole remain stable because of
highly efficient autoregulation?
A step change in RPP usually yields almost no change in
steady-state whole kidney RBF, GFR, efferent arteriolar
blood flow (956, 1636), or intrarenal hydrostatic pressures
FIGURE 3. Data redrawn from 6 published studies to illustrate different methods for assessing renal autoregulation or the contributions of
myogenic and macula densa-tubuloglomerular feedback (MD-TGF) mechanisms. A: measurements of renal blood flow (RBF) by electromagnetic
flow meter recordings in anesthetized rats as a function of induced changes in renal perfusion pressure (PP). The autoregulatory index (AI)
⬍0.05 implies almost perfect independence of RBF from renal PP across the range 105–145 mmHg (41, 46). B: study of dynamic renal
autoregulation in the time domain in anesthetized rats (749). The renal PP had been reduced previously by a suprarenal aortic clamp to ⬃95
mmHg. Abrupt release of the aortic clamp led to a rapid increase in renal PP (RPP) to ⬃110 mmHg, which was maintained throughout the 2
min. The renal vascular resistance (RVR) fell initially, but this was followed rapidly by a 3-component rise. Over the first 5 s, the increase restored
⬃50% of the final RVR response to the level of perfect autoregulation. This was attributed to the myogenic response (MR) and was followed over
10 –20 s by a further rise in RVR restoring ⬃35% of the RVR. This was attributed to macula densa-tubuloglomerular feedback (MD-TGF)
response and was followed by a third, slower component contributing ⬃15% of the final RVR response. C: study of dynamic renal autoregulation
in the frequency domain by transfer function analysis in rats of measurements of spontaneous changes of renal PP, measured by a pressure
transducer in the aorta, and RBF measured by ultrasonic blood flow meter (297). The tracing shows normalized admittance gain (a relative
autoregulatory index) as a function of frequency of spontaneous fluctuations in renal PP. Values at or above unity imply very weak to no active
autoregulation. Between 0.3 and 0.1 Hz oscillations in renal PP, the admittance gain fell steeply, corresponding to the myogenic response (MR).
There was a further sharp fall in admittance gain between 0.03 and 0.01 Hz, corresponding to the delayed MD-TGF mechanism. D:
measurements of the steady-state diameter of the afferent arteriole of the rat juxtamedullary nephron (JMN) preparation during induced
changes in renal PP (1020). An increase in renal PP, from 60 to 140 mmHg, reduced arteriolar diameter by ⬃25–30% (control). A progressive
autoregulatory reduction in diameter during increased renal PP was attenuated by blockade of MD-TGF (by furosemide) and was totally abolished
by the CCB nimodipine that eliminated all active tone. E: directly visualized changes in diameter of the rat afferent arteriole in the hydronephrotic
kidney (HNK) preparation lacking MD-TGF (586). An increase in renal PP from 80 to 180 mmHg reduced the arteriolar diameter (i.e., myogenic
response). F: development of active wall tension as a function of arteriolar PP in a mouse isolated perfused afferent arteriole (861). The slope
of this line defined the myogenic response over the PP range tested, and its intercept on the x-axis defined the threshold.
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RENAL AUTOREGULATORY MECHANISMS
(42, 276, 1167, 1188, 1241). Spontaneously hypertensive
rats (SHR) had excellent RBF and GFR autoregulation (41,
43, 465, 672, 706, 1247) and stable mean PGC and peritubular capillary pressures in their superficial cortical
nephrons, which were attributed to proportionate adjustments in preglomerular vascular resistance with RPP (42,
58, 394, 1064, 1247, 1564, 1567). Nevertheless, these SHR
displayed a pressure-natriuresis, albeit dampened compared with normotensive Wistar-Kyoto (WKY) rats that
also autoregulated efficiently (42, 276, 412, 808). Early
micropuncture studies reported that steady-state proximal
tubular reabsorption and fluid delivery to the distal tubule
of superficial cortical nephrons were maintained during an
acute change in RPP, implying minimal change in input
signal to modulate MD-TGF (42, 43, 342, 535, 901, 1067)
and minimal change in fractional Na⫹ delivery to the late
distal tubule in the superficial cortex (844). One in vivo
microperfusion study in rats reported that ⬃25 mmHg increase in RPP inhibited proximal Na⫹ reabsorption by almost 40%, but a similar decrease in RPP did not affect Na⫹
reabsorption (798). However, previous free-flow micropuncture studies from the same laboratory but in a different strain of rat reported unchanged proximal tubular
Na⫹ reabsorption of superficial nephrons, but decreased
reabsorption of deep nephrons, in response to increased
RPP (535).
Nevertheless, other investigators have reported that increased RPP inhibited Na⫹ reabsorption by the proximal
tubule of surface nephrons (248, 1245). Marsh, Roman,
and colleagues reported that increased RPP reduced proximal tubular reabsorption rapidly and increased fluid delivery to Henle’s loop despite highly efficient autoregulation of
RBF and GFR (249, 1248). Reduced absolute and fractional proximal tubular reabsorption after increased RPP
has been confirmed in other studies in rats, but autoregulatory efficiency was not verified (814, 995, 996).
A more consistent finding has been that increased RPP inhibits Na⫹ reabsorption by proximal tubules of deep
nephrons (to a greater extent than superficial nephrons)
(535, 1245). This likely reflects pressure-induced reductions in Na⫹ and fluid reabsorption in straight descending
portions of the late proximal tubule.
In studies in which an increased PP inhibited proximal tubular reabsorption, the anticipated increase in Cl⫺ reabsorption by Henle’s loop in response to the increased tubular fluid delivery was lacking (248, 249, 1245). Studies of
fractional Li⫹ excretion as an index of fractional proximal
Na⫹ reabsorption concluded that increased RPP reduces
fractional Na⫹ reabsorption in the proximal (536, 736) and
distal tubules (736). Increased RPP also reduced Na⫹ reabsorption by the nephron segments distal to Henle’s loop,
since pharmacological blockade of distal tubular Na⫹ reabsorption markedly attenuated the pressure-natriuresis re-
412
sponse (956). It is uncertain whether the medullary collecting duct (CD) also participates in these changes in reabsorption with PP (1245, 1394). Thus changes in Na⫹
reabsorption by Henle’s loop and the distal nephron can
participate in pressure-natriuresis.
The preglomerular vasculature of the juxtamedullary cortex maintained an appropriate myogenic and MD-TGF response that stabilized SNGFR in deep nephrons during increases in RPP (535, 1248). Similarly, the afferent arterioles
of the JMN preparation responded appropriately to
changes in PP (see below).
Nevertheless, the hydrostatic pressure in vasa recta capillaries and the cortical renal interstitial hydrostatic pressure
(RIHP), which in turn is thought to reduce tubular reabsorption, both increase with PP. An increase in RPP increased RIHP by only a few mmHg in nondiuretic rats, but
to a larger extent after volume expansion (459, 486, 524,
790, 792). Indeed, both the cortical and medullary RIHP
increased after volume expansion. Decapsulation of the
kidney reduced the changes in RIHP with PP and attenuated
pressure-natriuresis (459, 537, 791, 792). Changes in RIHP
independent of a change in RPP are commonly observed,
but may be more associative than causal since changes in
hydrostatic pressure are less influential on transepithelial
transport than changes in osmotic pressure (493, 539).
Since the efferent arterioles from the deep cortical nephrons
supply the medullary vasa recta capillaries, any attenuation
of autoregulation by the preglomerular vasculature of JMN
would likely transmit some of the changed RPP into the
vasa recta capillaries and the medullary interstitium. Consistent with this prediction, the hydrostatic pressure in vasa
recta capillaries was autoregulated less completely than in
renal cortical capillaries (1248).
Three factors have been identified that could increase the
medullary RIHP during increased PP in diuretic states. First,
the descending vasa recta provide a fourfold greater flow
resistance than the ascending vasa recta perhaps because of
the fewer descending capillaries that results in a markedly
lesser vascular cross-sectional area (71, 1149, 1643). Second, the hydrostatic pressure in the medulla is determined
primarily by the outflow resistance of the CDs (972). Third,
the descending vasa recta are surrounded by contractile
pericytes that can generate a myogenic response (908).
Large-diameter human outer medullary descending vasa
recta contracted to increased luminal pressure, whereas
smaller vasa recta did not (1348).
The medullary RIHP should determine the cortical RIHP
since the kidney is an encapsulated organ (277, 790, 1140).
Thus this sequence of events provides a mechanism
whereby cortical RIHP and proximal fluid reabsorption
could vary with RPP despite no change in PGC. Indeed, Na⫹
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CARLSTRÖM ET AL.
reabsorption was closely related to even very small changes
in cortical RIHP (1607).
Paracrine agents including NO, prostaglandins (PGs), 20HETE, and ATP have been proposed to modulate pressurenatriuresis. The slope of the natriuretic response to increased RPP is attenuated by inhibition of NOS (385, 411,
411, 429, 524, 666, 736, 946, 947, 955, 957, 959, 962,
963, 1277, 1476), or COX (190, 486, 536, 538, 797, 1074,
1258), or cytochrome P-450 4A to reduce 20-HETE generation (340, 1612). Moreover, renal interstitial ATP concentration paralleled RPP and regulated both MD-TGF (1090,
1091) and Na⫹ transport via epithelial sodium channels
(ENaC) in the CDs (1475).
Activation of AT1 receptors can inhibit pressure-natriuresis
(317, 321, 513, 515, 547, 569, 946, 995–997, 1074, 1258,
1516, 1549), whereas activation of AT2 receptors enhanced
pressure-natriuresis in some (514, 516) but not all studies
(911, 918). Inhibition of ACE-dependent ANG II generation enhanced pressure natriuresis (1074), whereas chronic
ANG II infusion increased BP and suppressed pressure natriuresis (1549). Moreover, clamping systemic ANG II levels during acute hypertension blunted the magnitude of the
pressure-natriuresis response (884). Increased RAS activity,
AVP (433), renal sympathetic nerve activity (RSNA) (328,
337, 376, 775, 806, 1130, 1382), and O2⫺ or hydrogen
peroxide (H2O2), especially in the renal medulla (273, 734,
1026, 1099), may also inhibit pressure natriuresis.
Despite this evidence of the importance of weak autoregulation of the medullary blood flow during volume expansion for initiating pressure-natriuresis, there remain two
divergent schools of thought concerning the major cause of
pressure-natriuresis in an autoregulating kidney with an
unchanged overall filtered load of Na⫹ and increased RIHP.
The major difference between them concerns the mediating
factor(s) and the relative importance of a primary change in
renal cortical NO generation or in medullary blood flow
(FIGURE 4, A AND B).
Majid and Navar demonstrated strong correlations between intrarenal levels of NO, RIHP, and pressure-natriuresis in dog kidneys exhibiting highly efficient autoregulation of cortical and medullary blood flow (FIGURE 4A) (955,
957–959, 961, 963). During changes in RPP, the Na⫹ excretion, renal cortical and medullary NO production, and
RIHP changed in parallel. Inhibition of renal NOS suppressed pressure-natriuresis in autoregulating kidneys without changing the filtered Na⫹ load (537). However, although administration of a NO donor during NOS inhibition increased basal Na⫹ excretion and RIHP, it failed to
normalize the slope of the pressure-natriuresis or RIHP relationships. This suggests that a combination of pressuredependent changes in renal NO production and RIHP are
required to mediate pressure-natriuresis.
A
Renal PP
Excellent corticol and medullary autoregulation
Vessel wall
shear stress
Arteriolar
vasoconstriction
Vascular
NO production
Interstitial
hydrostatic pressure
No change in
corticol or
medullary blood
flow or GFR
Tubular Na+ reabsorption
Renal Na+ excretion
B
Renal PP
Incomplete
medullary autoregulation
Excellent corticol
autoregulation
Medullary and
papillary blood flow
No change in corticol
blood flow or GFR
Medullary interstitial
hydrostatic pressure
Corticol interstitial
hydrostatic pressure
Na+ reabsorption
in the proximal
tubule
Renal Na+
excretion
FIGURE 4. Flow diagrams summarizing current hypotheses for
interactions between renal autoregulation and pressure natriuresis
in response to increased renal perfusion pressure (PP) with excellent autoregulation of cortical blood flow with and without efficient
autoregulation of medullary blood flow. A: proposed intrarenal
events causing pressure-natriuresis when both renal cortical and
medullary blood flows are excellently autoregulated. B: proposed
intrarenal events causing pressure-natriuresis when renal cortical
blood flow is excellently autoregulated but autoregulation of medullary blood flow is less complete. GFR, glomerular filtration rate; RBF,
renal blood flow; NO, nitric oxide; ROS, reactive oxygen species. For
details, see text (sect. IIA2).
Endothelial NO is released in response to increased vessel
wall shear stress. The constriction of the renal resistance
vessels during increased PP would increase wall stress without changing blood flow (171, 747, 1039, 1184, 1416,
1425) and could thereby provide a signal for NO release in
fully autoregulating kidneys. NO inhibits Na⫹ reabsorption in the TAL and the CDs (379, 460, 608, 1185, 1419),
whereas the actions in the proximal tubule are more controversial, with reports of NO inhibiting (1419) or stimu-
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413
RENAL AUTOREGULATORY MECHANISMS
lating (1560) Na⫹ reabsorption. However, studies in mice
with deletion of specific NOS isoforms concluded that NO
derived from nNOS or eNOS stimulated Na⫹ reabsorption and H⫹ secretion by the proximal tubule (1561).
Thus it is unlikely that the proximal tubule is the primary
site of NO-mediated inhibition of tubular reabsorption
during increased PP. As mentioned previously, blockade
of distal nephron Na⫹ transport markedly attenuated
pressure-natriuresis (956), demonstrating the importance of active transport inhibition in mediating this response. The TAL and the CD are rich sources of NO and
sites at which NO reduced Na⫹ reabsorption (1129,
1148, 1304, 1627). Indeed, medullary NO preferentially
inhibited Na⫹ reabsorption in the CDs (1304), which
participated in inhibition of fractional NaCl reabsorption during increased PP (1394).
Carey and colleagues have proposed a modified view for the
participation of NO in pressure natriuresis via effects on the
generation of cGMP and activation of PKG. Increased NOcGMP-PKG signaling modulated pressure-natriuresis during elevated PP by increasing RIHP and inhibiting proximal
tubular Na⫹ reabsorption independent of changes in GFR
or renal cortical or medullary blood flow (736, 737, 900).
Renal cortical interstitial cGMP accumulated in proximal
tubule cells where it activated PKG, inhibited tubular Na⫹
reabsorption, thereby increasing Na⫹ excretion independent of measurable hemodynamic changes (736, 737,
1153). This was regional specific since infusion of cGMP
into the renal cortex produced a natriuresis, whereas infusion into the renal medulla was ineffective (737).
Knox and colleagues presented evidence that increased RPP
increases prostaglandin E2 (PGE2) production by COX-1.
The PGE2 was believed to derive from endothelial cells of
the preglomerular vasculature and, during increased RIHP,
to inhibit proximal tubular Na⫹ reabsorption (486, 509,
536, 538, 790, 797, 823, 1207). The mechanism may involve PGE2-induced enhancement of paracellular Na⫹
backflux from the interstitium into the tubular lumen during increased RIHP that would decrease net Na⫹ reabsorption (1207). PGE2 also inhibited Na⫹ reabsorption by the
TAL and the CDs (37, 150, 151, 1061).
An alternative view of pressure natriuresis is based largely
on studies in the rat where there is reportedly less efficient
autoregulation of medullary and papillary blood flow during states of relatively high Na⫹ excretion (FIGURE 4B)
(277, 1248). Cowley, Mattson, Roman, and colleagues
have implicated medullary blood flow as a major determinant of Na⫹ excretion and BP (274, 277). They reported
that medullary blood flow and NO were reduced, and ROS
production was increased, during states of Na⫹ retention
and hypertension (275, 989, 991, 1670), whereas increased
medullary blood flow was associated with states of a low BP
(273, 274, 1014). NO could have a causal role also in the
414
medulla since its blockade attenuated the increases in renal
medullary blood flow and Na⫹ excretion during increased
RPP (411). An increased RPP in volume-expanded rats did
not change RBF, GFR, or SNGFR in either superficial or
deep cortical nephrons (1248). Nevertheless, proximal tubular reabsorption was decreased by 10%, and NaCl delivery to the bend of Henle’s loop of JMN was nearly doubled
(1245), thereby likely providing a signal to activate MDTGF. As is summarized in FIGURE 4B, these investigators
have demonstrated that RPP increases papillary blood flow
and vasa recta capillary hydrostatic pressure that is translated into an increased medullary RIHP which, after transmission to the cortex, reduces proximal tubular Na⫹ reabsorption. Increased Na⫹ delivery to the TAL of Henle’s
loop may stimulate production of O2⫺ which can be countered by flow-induced NO production by the vasa recta
capillaries. The balance of vasoconstrictor O2⫺ and vasodilator NO in the renal medulla is held to regulate the medullary blood flow by determining the degree of contraction
of pericytes in the outer medullary vasa recta, which, in
turn, can determine the strength of the pressure-natriuresis
(1099).
Moreover, the oxygen tension (PO2) of the renal parenchyma could also account for a relatively impaired medullary and papillary autoregulation. The kidneys have a high
O2 supply that is necessary to match the demand for tubular
O2 consumption related to active tubular Na⫹ reabsorption. The PO2 in the proximal and distal tubules, the efferent
arterioles, and the interstitium of the outer cortex of rat
kidneys were all similar and average 40 – 45 mmHg, indicating diffusional O2 equilibrium (1582). The PO2 in the
glomerulus, measured by a different technique, also averaged 45 mmHg (1331). These values were all lower than
PO2 measured in the renal vein (i.e., 55– 65 mmHg), indicating a preglomerular diffusional shunt for O2 between the
arterial and venous systems, likely via the arcuate vessels
(1605). This shunt stabilized renal cortical PO2 during
changes in arterial PO2 (883, 1605) but maintained a low
renal parenchymal PO2. The PO2 in the deep cortex and the
outer medulla of rat (FIGURE 5) (1260, 1582, 1583) and
mouse kidneys (860) was reduced to 30 – 40 mmHg. A
study in the rat hydronephrotic kidney (HNK) preparation
reported substantial reductions in the myogenic response as
the perfusate PO2 was reduced from 80 to 20 mmHg (936).
Thus a lower parenchymal PO2 in the medulla might contribute to a lower efficiency of the myogenic response (FIGURE 5) and thereby to the relatively impaired medullary
autoregulation. However, studies in dogs reported that
hypoxia (PO2 between 40 – 45 mmHg) did not affect autoregulation of RBF or GFR (26), but the diffusional O2 shunt
rendered renal PO2 largely independent of arterial PO2, at
least in the rat (1605). It remains to be demonstrated that
medullary PO2 varies with PP as would be required to modulate pressure natriuresis.
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CARLSTRÖM ET AL.
A
B
Myogenic responses and PO2
PO2 in
rat kidney
0
20
-10
30
40
-20
60
-30
PO2 (mmHg)
0
PO2 (mmHg)
Change in arteriolar diameter (%)
10
OC
IC
10
20
30
40
50
80
-40
80
120
140
160
180
PO2 in
mouse kidney
OC
OM
FIGURE 5. Oxygen tension (PO2) in different renal
compartments and its influence on the myogenic response of afferent arterioles. A depicts changes in
the diameter of afferent arterioles during increases in
renal PP (from 80 to 180 mmHg) in the atubular rat
HNK preparation (reflecting myogenic responses)
during perfusion with fluids of different PO2 ranging
from 20 to 80 mmHg. Note the graded impairment
of myogenic responses across the range of PO2 from
80 to 20 mmHg (936). B and C present values for
PO2 measured with microelectrodes in the kidney. In
B, PO2 values are shown for the outer cortex (OC) and
inner cortex (IC) in anesthetized rats (1582). In C,
PO2 values are shown for the outer cortex and outer
medulla (OM) of anesthetized mice (860).
Renal PP (mmHg)
In summary, the renal pressure-natriuresis response is important for control of ECV and BP. Although a rise in RIHP
and reduction in tubular reabsorption following an increase
in RPP are crucial events, the underlying mechanisms are
still debated. The contrasting two major hypotheses for
how the kidney senses a rise in RPP and generates a pressure-natriuresis, despite excellent autoregulation of the cortical nephrons, are summarized in FIGURE 4, A AND B. Functional abnormalities in disease models will be discussed
later in the sections on hypertension, CKD, and DM (see
sect. VII).
3. Conventional macula densa tubuloglomerular
feedback
The anatomical arrangement of different cell types in the
JGA that are involved in macula densa (MD)-mediated tubuloglomerular feedback (TGF) is shown schematically in
FIGURE 1. MD-TGF relates afferent arteriolar tone to MD
cell tubular electrolyte delivery and reabsorption. It can be
studied in superficial nephrons of anesthetized animals by
microperfusion of Henle’s loop with artificial tubular fluid
to vary NaCl reabsorption by the MD segment (48, 1066,
1075, 1305, 1316, 1513). Details about methodologies and
approaches to investigate MD-TGF by renal micropuncture
have been reviewed (923, 1311, 1513). Afferent arteriolar
responses have been assessed from changes in the SNGFR,
PGC, or proximal tubular stop-flow pressure (PSF) upstream
from an oil or wax block in the proximal tubule. MD-TGF
in longer deep cortical nephrons has been assessed in the
exposed papilla by perfusing fluid through the TAL of Henle’s loop and measuring glomerular responses at an upstream site of the same nephron (1042, 1043). The afferent
arteriole is the effector site, and its terminal segment is the
most responsive site for MD-TGF activation (200, 695,
703, 1020). Ambient MD-TGF activity has been assessed
from the difference in SNGFR measured from the proximal
tubule (which prevents activation of the MD) and the distal
tubule with MD function intact. This approach characterizes MD-TGF at zero and ambient, but not at supranormal
rates of tubular fluid flow.
The role of MD-TGF in autoregulation has been evaluated by measuring vascular function during changes in
RPP before and during inhibition of MD-TGF by blocking the flow of tubular fluid to the MD of the test nephron
or by blocking NKCC2 activation of MD cells with a
loop diuretic. Inhibition of MD function abolished the
effects of MD-TGF signaling on afferent arteriolar diameter, PGC, single-nephron blood flow, and GFR of superficial and deep cortical nephrons and attenuated autoregulation of SNGFR during changes in RPP (200, 1019,
1022, 1064, 1075, 1249, 1636). A contemporary approach has been to assess afferent arteriolar or glomerular responses using genetic mouse models that lack MDTGF such as the adenosine A1 receptor knockout (155,
205, 686, 1123, 1312, 1318, 1508) and other transgenic
models with impaired MD-TGF signaling (152, 496,
806, 942, 1093). Autoregulation was less complete after
inhibition of MD-TGF by genetic deletion of adenosine
A1 receptors (583, 751) or P2X1 receptors (686) or Cx40
(756, 1395), all of which impair MD-TGF responses.
Glomerular autoregulation has been reported to be less
efficient in the absence of MD-TGF in several species,
including rats (1019, 1022, 1313, 1444), dogs (351, 760,
1064, 1090, 1091, 1622), and mice (583). For example,
the MD-TGF in the rat contributed ⬃50% to autoregulation of SNGFR when the RPP was reduced from 115 to
95 mmHg and 30% when it was reduced from 95 to 80
mmHg (1313). Studies made in dogs indicated that a
reduction in RPP from 124 to 94 mmHg in kidneys in
which RBF and GFR were efficiently autoregulated led to
a 30% reduction in proximally measured SNGFR (when
flow to the MD is zero), whereas distally determined
SNGFR (when delivery to the MD is intact) was unchanged (1613). Steady-state RBF autoregulation was reduced ⬃50% in nonfiltering dog kidneys (1284). In mice,
a 15 mmHg reduction in RPP reduced RBF and GFR by 6
and 12%, respectively, but the adjustments were less
complete (with 15 and 40% respective reductions) in
mice lacking functional MD-TGF (583). Thus MD-TGF
clearly contributes to autoregulation of RBF and GFR.
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RENAL AUTOREGULATORY MECHANISMS
delay was ⬃30 s in the dog kidney (86). This response was
completed during the following 15–20 s in rodent kidneys
(FIGURE 3B) (296, 296, 629, 748, 749) or 20 – 40 s in dog
kidneys (748, 753). This delay sets up MD-TGF-based oscillations in proximal tubular pressure (PPT) at ⬃0.035 Hz
(626, 893, 1512) which are in phase with fluctuations in
early distal tubule fluid flow and [Cl⫺] that are signals for
activation of MD-TGF. All of these cycled at 25–35 s (35
mHz) (627). Measurement of these oscillations has been
used to assess endogenous MD-TGF activity during
changes in RPP.
Afferent arteriolar autoregulatory responses in the JMN
preparation were reduced 25–50% by elimination of MDTGF by papillectomy or furosemide in the rat (686, 1028,
1364, 1437) or mouse (686, 687). Papillectomy or tubular
oil block inhibited afferent arteriolar responses similar to
that of furosemide, indicating that the primary effect of
furosemide in this preparation was on MD transport and
not directly on the afferent arteriole. However, furosemide
also attenuated the autoregulation of GFR when measured
in proximal tubules in the JMN preparation, which prevents delivery of tubular fluid to the MD and negates the
MD-TGF (200, 1022). This might represent nephronnephron interactions whereby inhibition of MD-TGF in
neighboring nephrons attenuates the myogenic response in
the test nephron. Other studies reported that furosemide
abolished pressure-dependent autoregulation of afferent arterioles in the JMN preparation (485). Furosemide also inhibited MD-TGF-mediated constriction of the afferent arteriole in the doubly perfused, isolated JGA (695). These
studies reinforce the conclusion that MD-TGF contributes
importantly to renal autoregulation.
A number of vasoactive factors may link MD transport of
electrolytes by the NKCC2 cotransporter, ROMK channel,
Na⫹/H⫹ exchanger, and Na⫹-K⫹-ATPase to the release of
vasoconstrictors including ATP, adenosine, PGH2, TxA2, and
O2⫺ and vasodilators such as NO, PGE2, and carbon monoxide (CO) to modulate afferent arteriolar tone (FIGURE 6). The
following sections discuss the role of purinergic signaling
molecules (e.g., ATP and adenosine) in regulation of MDTGF and renal autoregulation, and the role of Cxs and
extraglomerular mesangial cells.
MD-TGF in rodent kidneys had a delay of 10 –15 s before
initiation of a PSF response following a rapid step change in
RPP and increased tubular fluid flow (87, 296, 1547); the
A) ATP RECEPTOR SIGNALING.
ATP can be released into the
interstitium by activated MD cells (83, 203, 1064, 1510);
Renal PP
Connecting tubule NaCl delivery
Macula densa NaCl delivery
ENaC transport
NO
NKCC2 transport
Na+/H+ exchange
EETS
PGE2
NO
O2·-
PGH2
TxA2
Adenosine
ATP
PGE2
Afferent arteriolar tone
FIGURE 6. Flow diagram for the modulation of renal afferent arteriolar tone by conventional macula densa
tubuloglomerular feedback (MD-TGF) and connecting tubule glomerular feedback (CT-GF). Changes in renal
perfusion pressure (PP) are transduced by alterations in tubular fluid NaCl delivery to the MD and the CT.
Subsequent changes in tubular transport lead to release of specific mediators and modulators that impact on
afferent arteriolar vasomotor tone. Vasoconstrictor agents increase (⫹) arteriolar tone. Vasodilator agents
reduce (⫺) arteriolar tone. ENaC, epithelial Na⫹ channel; NKCC2, Na⫹-K⫹-Cl⫺ cotransporter; EETs, epoxyeicosatrienoic acids; PGE2, prostaglandin E2; NO, nitric oxide; O2·⫺, superoxide; PGH2, prostaglandin H2; TxA2,
thromboxane A2; ATP, adenosine triphosphate; CO, carbon monoxide. For details, see text (sects. IID and VIE ).
416
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CARLSTRÖM ET AL.
however, uncertainty exists regarding the mechanism(s) of
the associated vasoconstriction of the parent afferent arteriole (FIGURE 6). ATP is thought to directly activate P2 receptors on the afferent arteriole or to activate different purinergic receptors on extraglomerular mesangial cells to initiate a Ca2⫹ wave that is transmitted to the afferent arteriole
through gap junctional coupling (83, 85, 682, 1071, 1176).
Alternatively, ATP and AMP may activate MD-TGF indirectly following metabolism by nucleotidases to adenosine
(1510) (discussed in sect. IIA3B). ATP, adenosine, and other
endogenous agents can activate vasoconstrictor purinergic
homomeric P2X1, heteromeric P2X1/4, or adenosine A1 receptors, respectively, on preglomerular VSMCs (521, 565,
1510, 1540). Activation of P2X receptors by ATP induced
ligand-gated cation influx, membrane depolarization, and
Ca2⫹ entry via VOCCs that were reinforced by inositol
trisphosphate (IP3) receptor-mediated Ca2⫹ mobilization
(565, 683, 685, 1197). Studies examining the potential role
of P2X receptors in renal autoregulation, in particular MDTGF responses in different nephron populations, have
yielded conflicting results. ATP and P2X1 receptors are required for MD-TGF responses in JMN of both rats and
mice (683, 686, 690). Knockout of P2X1 receptors attenuated MD-TGF responses and the contribution of MD-TGF
to autoregulation of total or juxtamedullary blood flow
(686). In one rat study, peritubular capillary infusion of
ATP caused transient reduction in PSF and attenuated subsequent maximal MD-TGF response of superficial
nephrons by more than 80% (1013). Continuous administration of ATP caused P2X receptor desensitization and attenuated MD-TGF, suggesting that P2 receptor signaling
participated in MD-TGF (1013). However, emerging evidence from assessment of MD-TGF in superficial nephrons
elicited by elevated loop flows in vivo does not support a
role for P2 receptors in superficial nephrons. For example,
PSF measurements revealed normal MD-TGF in mice lacking P2X1 receptors (1312), and administration of the P2
receptor inhibitors PPADS or suramin did not alter the PSF
response (1306).
Stepwise reductions in RPP in dogs elicited parallel reductions in whole kidney RVR and renal cortical interstitial
ATP concentration (1090). Moreover, stimulation of MDTGF by increasing distal fluid delivery using acetazolamide
increased renal interstitial ATP, whereas blockade of MD
reabsorption with furosemide reduced ATP and renal autoregulation (1091). Thus a positive correlation between interstitial ATP and RVR adjustments has been demonstrated, and changes in ATP concentration could provide a
renal interstitial signal of changed RPP and an effector
agent for vasoconstriction by activation of purinergic signaling. Desensitization, saturation, or blockade of the P2purinoceptors attenuated whole kidney (952, 1131, 1438)
or nephron autoregulation via blockade of the MD-TGF
(683, 686, 690). Available evidence indicates that P2X1 receptors participate in renal autoregulation primarily by reg-
ulation of the MD-TGF mechanism in the JMN (203, 683,
1065, 1312, 1510).
In contrast to the renal microcirculation, myogenic autoregulation in the cerebral vasculature depended strongly on
P2Y4 and P2Y6 pyrimidine receptors (142). Pharmacological blockade or molecular suppression of either of these P2
receptors using antisense oligodeoxynucleotides reduced
myogenic constrictor tone by ⬃45%. Thus the roles of purinergic agonists and receptors in autoregulation vary according to the vascular bed.
B) ADENOSINE RECEPTOR SIGNALING. Other studies strongly implicate adenosine in the MD-TGF regulation of RBF, GFR,
and PGC (203, 1316, 1459, 1510, 1511). Vasoconstriction
occurs primarily via activation of adenosine A1 receptors on
the afferent arteriole (155, 778, 1216, 1316, 1320, 1426,
1540), but A1 receptors on mesangial cells also may modulate Ca2⫹ signaling (1122). Activation of high-affinity A1
receptors caused vasoconstriction by stimulation of G␣i
proteins that inhibited cAMP production and by activation
of phospholipase C (PLC) that liberated IP3 and mobilized
intracellular Ca2⫹ (555, 1510). Activation of the lower affinity adenosine A2 receptors elicited vasodilatation by
stimulation of G␣s proteins that activated the cAMP/protein kinase A (PKA) pathway and stimulated NOS (188,
555, 557). A2 receptor activation attenuated PP-induced
arteriolar vasoconstriction by opening KATP channels to
cause hyperpolarization of the plasma membrane (1450).
A2 receptor-mediated vasodilation during MD-TGF can
oppose A1 receptor-induced vasoconstriction (187, 188).
Maximum stimulation of A2 receptors impaired renal autoregulation of afferent arteriolar tone in one study (409), but
not of whole kidney RBF in another (1198).
Adenosine formed by nucleotidase metabolism of ATP and
AMP mediates the MD-TGF response in superficial
nephrons of mice (205, 647, 1123, 1459). A1 receptor antagonists inhibit MD-TGF markedly (1320). Mice genetically deficient in A1 receptors lacked MD-TGF in superficial
nephrons (155, 1426), whereas MD-TGF was enhanced in
mice overexpressing A1 receptors (1125). Steady-state autoregulation of RBF was reduced by 40 –50% in A1⫺/⫺ mice
(583, 751). This was ascribed to a weaker contribution of
MD-TGF while the myogenic component was well preserved. Selective deletion of A1 receptors in VSMCs reduced
MD-TGF responsiveness by 65%, thereby demonstrating
that the main effect of A1 receptors is to mediate MD-TGFinduced afferent arteriolar vasoconstriction rather than to
activate MD cells or enhance signal transmission through
extraglomerular mesangial cells (896, 1122). Thus activation of A1 receptors mediates MD-TGF in superficial
nephrons and contributes significantly to autoregulation in
rodents, but these receptors are probably not required for
the myogenic response. Pharmacological blockade of vascular A1 receptors in the isolated rabbit JGA preparation
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RENAL AUTOREGULATORY MECHANISMS
abolished MD-TGF (1216), similar to inhibition of 5’-nucleotidase conversion of AMP to adenosine (1229).
However, some pharmacological studies in dogs, rats, and
mice failed to detect a major role of adenosine or A1 receptors in MD-TGF signaling or afferent arteriolar autoregulatory responses (438, 686). Systemic administration of an
A1 receptor antagonist did not impair RBF autoregulation
in the dog kidney (654) and did not blunt PP-induced
changes in afferent arteriolar diameter in the mouse JMN
preparation (686). Propagation of a MD-TGF-induced
Ca2⫹ wave along the afferent arteriole in rats also was
unaffected by A1 receptor blockade (1176).
In summary, activated MD cells release ATP that can be
metabolized to adenosine. Uncertainties about the roles of
adenosine and A1 receptors and ATP and P2X1 receptors in
preglomerular autoregulatory responses to MD activation
are based on controversies concerning their respective contributions to MD-TGF. There are studies supporting an
involvement of both adenosine and ATP in the MD-TGF
response, and contrasting conclusions may be explained by
different experimental designs or perhaps by regional differences in ATP and adenosine signaling within the kidney.
Available evidence demonstrates that P2X1 receptors participate in renal autoregulation primarily by regulation of
the MD-TGF mechanism in JMN, whereas A1 receptors are
essential for MD-TGF responses in superficial nephrons.
Nevertheless, it seems clear that neither of these purinergic
agents nor their specific receptors mediates the renal myogenic response.
C) CXS AND EXTRAGLOMERULAR MESANGIAL CELLS. Cxs form gap
junctions to connect cells. They provide intercellular channels that can facilitate the exchange of ions, second messengers, electrical signals, and metabolites. Cxs coupled multiple cell types in the JGA in the kidney, including endothelial, VSMCs, and juxtaglomerular granular cells (JGC)
(553, 1545). The preglomerular vasculature and the JGA
expressed primarily Cx37, Cx40, Cx43, and Cx45 (50,
553, 1439, 1546). Cx40 predominated in endothelial cells
and Cx45 in VSMCs (553), although the latter has been
questioned (1296). The endothelium of the proximal afferent arteriole possessed all of these Cxs, whereas the VSMCs
in the terminal segment of the arteriole expressed only
Cx40. Moreover, Cx40 was the major isoform in the JGA
where it was expressed on endothelial cells, granular reninproducing cells, and extraglomerular mesangial cells. However, MD cells lacked Cxs, and therefore any effects of
Cx40 on autoregulation likely involved transmission of
MD-TGF signals to the afferent arteriole.
Destruction of glomerular mesangial cells in rats by mesangiolysis or pharmacological disruption of gap junctions prevented MD-TGF responses (1218) and impaired GFR autoregulation (706, 1438), but left RBF autoregulation rela-
418
tively intact (706). Administration of 5’-nucleotidase
improved GFR autoregulation following mesangiolysis, implicating attenuated adenosine signaling in the impaired
GFR autoregulation (1444).
Putative inhibitory peptides directed against specific Cxs
have implicated them in autoregulation, but have not yet
distinguished between myogenic and MD-TGF mechanisms. Blockade of Cx37 and Cx40, but not Cx43, in normal rats increased the BP and reduced RBF autoregulation
(1439), whereas blockade of Cx37, Cx40, or Cx43 all impaired the RBF autoregulation in Zucker lean rats (1441).
Cx37 and Cx40 in Zucker lean rats were implicated in
transducing purinergic signals involved in autoregulatory
responses, likely involving MD-TGF (1438). RBF autoregulation following putative Cx inhibition was improved by
increasing adenosine production from AMP with 5’-nucleotidase.
There is some concern about the specificity of inhibitors of
gap junction function. Nonspecific effects of the gap junction inhibitors heptanol and 18␤-glycyrrhetinic acid have
been noted even at concentrations that have no or little
effect on gap junctions (979). Cx-mimetic peptides appear
to be more selective in inhibiting gap junctions. However,
the most definitive results have derived from Cx gene-deleted mice.
Genetic deletion of Cx40 and Cx43 increased renin synthesis and secretion and disrupted the regulation of renin
release by intravascular pressure and ANG II (545,
1546). Restoration of Cx40 in renin-producing JGC but
not endothelial cells reduced hypertension and renin secretion of Cx40 null mice (879). Cx40 knockout mice
had impaired whole kidney RBF autoregulation with a
markedly reduced MD-TGF component (756). However,
they retained an unchanged myogenic and third mechanism and a preserved dampening of the myogenic response by NO. Thus Cx40 contributes to RBF autoregulation via MD-TGF-mediated signal transduction from
the MD. This is independent of NO but likely includes
traffic across extraglomerular mesangial cells that are
heavily endowed with Cx40 (756). These findings and
conclusions are supported by the disruption of autoregulatory adjustments of the afferent arteriole in the JMN
preparation in Cx40-deficient mice (1395). These mice
lack the MD-TGF mechanism, whereas the myogenic response is preserved. Micropuncture studies of superficial
nephrons in kidneys lacking Cx40 demonstrated 50%
attenuation in MD-TGF (1122). In contrast, Cx37-deficient mice retain a highly efficient RBF autoregulation
with normal contributions of myogenic and MD-TGF
components (A. Just, personal communication). Thus
Cx40 appears to be a key element for transmission of
MD-TGF signal(s) that contribute to renal autoregulation.
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CARLSTRÖM ET AL.
Conducted vasomotor responses in preglomerular arterioles are mediated largely by passive electronic spread of the
EM transmitted through gap junctions in the arteriolar wall
connecting endothelial cells and/or VSMCs, but the specific
Cxs involved remain controversial. Electrically induced
Ca2⫹ responses conducted along rat isolated cortical radial
arteries were preserved after inhibitory peptides directed
against Cx37, 40, 43, and 45 (1399), whereas propagation
in mice was abolished by genetic deletion of Cx40 (1395).
Interestingly, the Ca2⫹ response to NE along this arterial
segment was unaffected by deletion of Cx40. In vivo studies
demonstrated that vasoconstriction produced by NE, or
vasodilation elicited by acetylcholine (ACh), was preserved
in the renal vasculature of mice lacking Cx40 (756). Moreover, mechanical stimulation of cultured glomerular endothelial cells triggered a Ca2⫹ wave propagated from cell to
cell, which was dependent on Cx40, extracellular ATP, and
P2 receptors, but was independent of L-type VOCCs
(1473). On the other hand, the propagation of mechanically
induced Ca2⫹ waves was slower in cultured VSMCs deficient in Cx45 and in control VSMCs treated with a peptide
that inhibited Cx45 gap junctional communication (554).
Direct gap junction coupling was suggested since Ca2⫹
wave propagation was unaffected by the ATP P2 receptor
blocker suramin. In contrast, VSMC-specific deletion of
Cx45 did not affect conduction of vasomotor responses to
high KCl, ACh, or adenosine along the VSMC layer of
mouse cremaster arterioles tested in vivo (1296). A Ca2⫹
wave originating by activation of MD cells and passing
through extraglomerular mesangial cells was dependent on
ATP and P2 receptors and was blocked by pharmacological
uncoupling of gap junctions (1176). ATP traversed Cx43
hemichannels in astrocytes (766). As discussed in more detail in section VIG, major differences have been noted between positive in vitro and negative in vivo findings in these
studies.
The Cx-like channel pannexin 1 was expressed in VSMCs
of mouse afferent and efferent arterioles and may play a role
in purinergic signaling (552). Pannexin 1 also was localized
to the apical membrane of several tubular segments where it
mediated ATP release into tubular fluid.
Gap junctional communication has been implicated in myogenic responses of nonrenal arteries. Nonselective inhibition of gap junctions attenuated myogenic contractions of
cerebral arteries (856), whereas inhibition of Cx37 and
Cx43 attenuated myogenic vasoconstriction of rat mesenteric resistance arteries (369). VSMCs were hyperpolarized
and had diminished changes in [Ca2⫹]i. Although gap junctions mediated pressure-induced VSMC cell depolarization,
changes in [Ca2⫹]i and myogenic vasoconstriction in vitro,
they were not required for vasoconstriction to PE. Genetic
alteration of Cx40 in endothelial cells of mouse mesenteric
arteries demonstrated its role in transmission of electrical
(but not chemical) signals that increased the sensitivity of
the myogenic response (215).
In summary, in vivo and in vitro observations suggest a role
for gap junctions and Cxs, particularly Cx40, in MD-TGF
signaling to the afferent arteriolar cells via mesangial cells.
Further studies are required to elucidate how Cxs, either as
monomers or multimers, coordinate MD-TGF signal transmission and renal autoregulation. Cxs also are implicated in
Ca2⫹ signaling and electrotonic and purinergic signaling
along the preglomerular vasculature which may participate
in nephron synchronization and renal autoregulation. The
initial signaling between MD and JGC is diffusive while
transmission from JGC to the AA is mainly electrotonic.
The role of Cxs in modulating autoregulation is also discussed in section VIG.
4. Dynamics of autoregulatory responses
Steady-state assessments of RBF autoregulation in response
to graded changes in RPP have been used widely to study
the effectiveness of autoregulation and the range of RPP
over which autoregulation takes place (FIGURE 3A). Dynamic analyses allow a more detailed evaluation of the contributions of individual underlying mechanisms to the overall adjustments in vascular resistance or admittance.
A) STUDIES IN THE TIME DOMAIN.
Measurements of dynamic
responses of RVR in the time domain have employed a
sudden, single-step change in RPP within the autoregulatory range. Such studies revealed a fingerprint of distinct
intrarenal mechanisms as a function of time after the change
in RPP based on clearly separable time constants with
minimal nonlinear interactions. A rapid 20 mmHg step increase in RPP led to a biphasic or triphasic increase in RVR in
dogs (753, 755, 1465, 1578), rats (423, 748 –750, 756,
1313, 1342, 1640), and mice (299, 462, 505, 751, 756).
This approach separated the most rapid myogenic component (0 – 8 s in rodents) from the slower MD-TGF component
(10 –30 s in rodents) (FIGURE 3B) (748, 749, 753). The early
myogenic response was initiated by an immediate change in
transmural pressure since a similar rapid response followed a
step reduction of extravascular tissue pressure (57, 265). The
onset of the MD-TGF-dependent changes in RVR was delayed by 10 –15 s and completed within 20 –30 s in rodent
kidneys (FIGURE 3B) (296, 749, 1547) and within 30 – 45 s
in dog kidneys (753).
Autoregulatory kinetics have been characterized in normal
rats using the isolated, blood-perfused JMN preparation. A
50 mmHg increase in RPP elicited a biphasic contractile
response with a transition point at ⬃24 s. In the absence of
MD-TGF (papillectomy), the response of myogenic origin
retained the same rate of contraction but terminated 11 s
earlier at 13 versus 24 s with intact MD-TGF (1547), suggesting that MD-TGF enhances the myogenic mechanism
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RENAL AUTOREGULATORY MECHANISMS
by prolonging its response. This important study by Walker
and Navar is discussed in more detail in section IIC.
Additional autoregulatory mechanisms have been identified
recently. A third mechanism has been proposed to increase
RVR progressively from 30 to 120 s after the abrupt increase in RPP. It contributed 10 –20% to overall autoregulation in mice and rats (FIGURE 3B) and 30% in dogs (299,
749, 751, 753, 1626). Its participation may increase at low
RPP in the rat (749). It was preserved in knockout mice
lacking neuronal NOS, inducible NOS, and adenosine A1
receptors (299, 751) and was independent of MD-TGF in
some, but not all, studies (749 –751, 753). The mediators of
this response are unclear, but may reflect an interaction
of known mechanisms, a delayed engagement of MD-TGF
of long JMN, a contribution of renal autocrine/paracrine
factors, or a component of pressure-natriuresis. ATP and
P2X1 receptors may also mediate the third mechanism, or
perhaps ANG II acting on AT1 receptors (284, 491, 1397).
Inhibition of MD-TGF by drugs or by genetic deletion of
adenosine A1 receptors unmasked an apparent fourth
mechanism that operated within the 5- to 25-s time window
after an abrupt increase in RPP and contributed ⬃25% to
overall autoregulation (751). This time-frame overlapped
that of the conventional MD-TGF and was unmasked only
when MD-TGF was prevented by furosemide. However,
some MD-TGF might operate independent of furosemidesensitive NKCC2 cotransport, perhaps modulated by a
Na/H exchanger in MD cells (84, 431, 800, 1177, 1178,
1210).
The influence of the connecting tubule glomerular feedback
(CT-GF) vasodilator system, involving Na⫹ reabsorption
via ENaC in the CT, is presently unclear. However, a vasodilatory phase observed 60 –200 s after a step increase in
RPP in the rat (1342) may represent the contribution of the
CT-GF (see sect. IIB2). Thus a third, and possibly a fourth,
mechanism may contribute to renal autoregulation in the
dog, rat, and mouse kidneys. Their importance and underlying signaling pathways require further study.
Several rat studies have characterized dynamic adjustments
of the renal vasculature following a brief period of complete
occlusion of the aorta (1342, 1397, 1398, 1626), but this
evoked metabolic and vasoactive factors, in addition to basic pressure-dependent autoregulatory mechanisms. Studies
in the rat of complete renal ischemia for 30 s followed by a
rapid single step increase in RPP reported time-dependent
oscillations in the RBF responses at ⬃10, 35, and 115 s,
reflecting the operation of three distinct autoregulatory
mechanisms (1626), likely the myogenic, MD-TGF, and
third mechanisms.
A strength of dynamic analysis of vascular adjustments in
the time domain is that in addition to providing useful in-
420
sight into individual mechanisms and their relative conributions, it provides reliable quantiative data for total autoregulation that agree with steady-state AI values for RBF autoregulation.
B) STUDIES IN THE FREQUENCY DOMAIN. Kidneys normally exhibit oscillations in microvascular tone. Transfer function
analyses of the gain of renal vascular admittance (the reciprocal of impedance and similar to steady-state conductance
that is the reciprocal of resistance) to spontaneous or imposed changes in RPP can distinguish between autoregulatory components in the frequency domain (19, 230, 297,
629, 631, 722, 971, 1274, 1357, 1358, 1563, 1569, 1570).
This has been investigated in conscious dogs (753, 755,
760, 1618), mice (668), rabbits (722), and rats (927, 1182,
1183, 1376). Renal autoregulation in conscious animals is
efficient and similar to that recorded using the same methodology under anesthesia. One discordant study reported
no blood flow autoregulation in the kidneys of conscious
rats during spontaneous fluctuations in BP between 0.03
and 2 Hz (723).
An admittance gain of less than 0 dB or a relative normalized admittance gain of 1.0 (analogous to an AI of 1.0)
indicates active autoregulatory adjustments within the vasculature to minimize RBF changes during fluctuations in
RPP. An admittance gain above 0 dB or 1.0 relative unit
implies that passive vascular elasticity contributes to the
amplification of the effect of RPP fluctuations on RBF. A
lower relative value between 1.0 and zero quantitates the
relative strength of overall autoregulation with the fractional variation in RBF being smaller than that of the RPP.
As with AI, a normalized admittance gain of zero indicates
perfect autoregulation. A representative recording of normalized admittance gain as a function of frequency for normal rats is shown in FIGURE 3C (297). Interpretation of
admittance gain commonly is best achieved by reading from
right to left, from high to low frequencies. A decline in the
gain values indicates the onset of an active contribution to
autoregulation. With the use of this methodology, the myogenic mechanism operating in the 0.20 – 0.10 Hz frequency
band accounts for ⬃65% of total autoregulation of RBF,
whereas the MD-TGF mechanism in the 0.04 – 0.011 Hz
frequency band appeared to contribute ⬃35% of total autoregulation. The slower apparent third mechanism operates at frequencies of ⬃0.01 Hz and below which is below
the frequency range normally examined with confidence.
Most studies of dynamic autoregulation utilizing frequency
analysis have reported that the myogenic response in normal
rat kidneys reduces the admittance gain from approximately
⫹7.5 to ⫺5 dB (or fraction gain from ⬃2.3 to 0.56) over the
frequency range of 0.20 to 0.07 Hz, whereas the MD-TGF
response reduces the admittance gain by a lesser degree from
⫺2.5 to ⫺12.5 dB (fractional gain from 0.75 to 0.24) over the
frequency range 0.05 to 0.020 Hz (FIGURE 7B). Summarized
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CARLSTRÖM ET AL.
B
RVR after a step increases in renal PP
150
100
50
Control
L-NAME
0
Frequency domain analysis
Admittance gain (dB)
RVR (percent of
perfect autoregulation)
A
15
10
5
0
-5
Control
L-NAME
-10
-15
-50
0
5 10 15 20 25 30 35 40 45
50 55 60
0.01
Time after renal PP increase (sec)
Afferent arteriolar
diameter (µm)
24
Afferent arteriolar myogenic
response in HNK
20
16
12
Control
L-NAME
8
4
80
100
120
140
160
180
Perfusion Pressure (mmHg)
D
Change in afferent
arteriolar diameter (µm)
C
0.1
1
Frequency (Hz)
Juxtamedullary
nephron preparation
0
-10
-20
-30
Control
L-SMTC
-40
100
130
160
Perfusion Pressure (mmHg)
FIGURE 7. Effect of nitric oxide synthase (NOS) inhibition of renal autoregulation mediated by myogenic and
macula densa tubuloglomerular feedback (MD-TGF) mechanisms. Illustrations of the effects of inhibition of NOS
with L-nitro-arginine methyl ester (L-NAME) on whole kidney autoregulation or renal blood flow (RBF), renal
vascular resistance (RVR), and myogenic responses of individual vessel segments. A depicts time-dependent
changes in RVR in rat kidneys following an abrupt step increase in renal perfusion pressure (PP) by release of
a suprarenal aortic clamp at time zero. After generalized inhibition of NOS with L-NAME, the initial increase in
RVR (corresponding to the myogenic response over the first 5 s) was greatly exaggerated and accounted for
almost all of the autoregulatory increase in RVR without major contributions of other autoregulatory components, such as the MD-TGF component seen in control kidneys from 5 to 25 s or the more delayed and gradual
third component thereafter (750). B shows the effect of general NOS inhibition with L-NAME on the transfer
function analysis of the admittance gain as a function of frequency for spontaneous changes in renal PP and
RBF in rat kidneys. After inhibition of NOS with L-NAME, the reduction in admittance between 0.07 and 0.2 Hz
(corresponding to the myogenic response) was much more abrupt and the regression of admittance on
frequency was steeper. Whereas control rat kidneys had a second reduction in admittance between 0.03 and
0.01 Hz (corresponding to the MD-TGF), this was hard to distinguish from the myogenic change in admittance
after L-NAME (1358). C depicts changes in the diameter of the afferent arterioles of the rat hydronephrotic
kidney (HNK) preparation as a function of renal PP. The decline in diameter with increasing renal PP (myogenic
response) was similar in control rats and those given L-NAME, indicating no change in the myogenic response
in this preparation that lacks renal tubules and MD cells (1358). D shows the change in afferent arteriolar
diameter in the rat JMN preparation to increased renal PP before and after inhibition of nNOS with SMTC
(S-methyl-L-thiocitruline) (662). The arteriolar autoregulatory response was increased after inhibition of MD
nNOS.
data for gain expressed in dB are from References 19, 286,
297, 629, 631, 748, 749, 1358, 1570. Data for fractional
gain are from References 109, 499, 1193. The myogenic
response in the kidneys of conscious mice reduces the admittance gain from ⫹7 to ⫺4 dB over the frequency range
of 0.3 to 0.1 Hz, whereas MD-TGF reduces the gain from
⫺1 to ⫺5 dB over the range of 0.04 to 0.01Hz (668). Thus
the myogenic mechanism provides the majority of the buffering of spontaneous fluctuations in RPP in rats and mice.
An early comparison of methodologies in conscious resting
dogs revealed that stepwise changes in mean RPP produced
stronger RBF autoregulation than overall autoregulation
analyzed by the transfer function admittance gain during
spontaneous fluctuations in RPP (760). Dynamic autoregu-
lation measured by the transfer function was only one-third
as strong as steady-state adjustments produced by the step
changes (⫺6.3 vs. ⫺19.5 dB). Just et al. (760) concluded
that MD-TGF was not required for RBF autoregulation
under normal physiological conditions, but contributed
during more extreme changes in PP.
Simultaneous measurements of steady-state RBF autoregulation and frequency domain analysis of whole kidney autoregulation in normal rats confirmed these methodological
differences and yielded disparate AIs of 0.2 and 0.4, respectively (109). Moreover, the methodological differences
were more pronounced in rats with reduced renal mass
(RRM). Whereas steady-state RBF autoregulation in 3/4
nephrectomized (Nx) rats was reduced compared with uni-
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RENAL AUTOREGULATORY MECHANISMS
nephrectomized (UNx) or control rats (AIs: 0.7 vs. 0.2 or
0.1, respectively), frequency analysis revealed no defect in
autoregulatory efficiency, with fractional admittance gain
of 0.4 – 0.5 at very low frequencies in all three groups (109).
Such a methodological difference may represent insensitivity of admittance analysis at low frequencies (⬍0.05 Hz)
compounded by low coherence of RBF and PP determinations at these frequencies and the inclusion of time points
when RPP is below the lower limit of renal autoregulation.
Moreover, caution should be taken when interpreting dynamics at low PP, since this may interfere with natural
operating frequencies of the myogenic and MD-TGF components resulting in added complexity due to nonlinear dynamics, interactions, and time-dependent variability, as discussed in section IIC. Another considerations is that the
steady-state method assesses predominantly the response of
RVR to mean RPP, whereas the dynamic method assesses
primarily the admittance response to slow fluctuations in
RPP (⬍0.25 Hz), which constitute a substantially smaller
component of the total BP power. Bidani, Griffin, and associates (108, 109, 496, 499, 933) concluded the steadystate results were more accurate depictions of the overall
impaired autoregulation that leads to hypertensive glomerular damage after RRM. More systematic comparisons of
the characteristics and contributions of intrarenal mechanisms and their interactions need to be made using these
different approaches. Such results will advance the field by
providing a better understanding of the strengths and weaknesses of the static and dynamic methodologies.
Most frequency domain studies have found that normalized
admittance gain is close to unity (or 0 dB) or greater for
frequencies ⬎0.3 Hz, indicating little autoregulation and a
passive, compliant vasculature (FIGURE 3C) (286, 297, 629,
748). Nevertheless, one study reported that forcing of RPP
between 1 and 6 Hz produced strong, sustained adjustments in afferent arteriolar diameter in the HNK preparation (927). Renal autoregulation clearly acts normally as a
high-pass filter in adjusting afferent arteriolar diameter to
limit changes in PGC caused by fluctuations in RPP. PGC has
a pulse pressure of 7–10 mmHg which is roughly one-third
of arterial BP pulsations (47, 148, 347). This demonstrates
damping of the very rapid pulsations at heart rate frequencies prior to pressure transmission into the glomerulus, as is
expected from the known preglomerular resistance. Nevertheless, high systolic BP may periodically exceed the autoregulatory limit and thereby contribute to glomerular injury
and eventual fibrosis (108, 282).
Dynamic analysis reported an active 0.01- to 0.02-Hz lowfrequency component of RBF autoregulation in conscious
and anesthetized rats, which may represent the third mechanism (753, 755, 1375). An early study with limited ability
to quantify fast events (⬎0.08 Hz) reported an apparent
fourth mechanism operating in the 0.04 – 0.08 Hz frequency band in the dog (1618).
422
An advantage of the admittance analysis is that it can reveal
the contributions of myogenic and MD-TGF mechanisms
without necessitating blockade of MD-TGF. However, a
limitation is that it does not provide absolute values for the
relative strengths, especially of MD-TGF and slower frequency components (109, 289, 297, 631, 1313).
Oscillations of arteriolar blood flow and PPT in the renal
cortex were synchronous with oscillations of total RBF
(1636), indicating that they originate from the vasculature.
Recordings of SNBF in the efferent arteriole by laser Doppler flowmetry and of PPT in nephron pairs from the surface
of rat kidneys identified two oscillatory modes: a faster (0.1
to 0.2 Hz) myogenic mode and a slower (0.02– 0.05 Hz)
MD-TGF mode. A third oscillation at 0.0125– 0.0130 Hz
was thought to reflect an interaction between MD-TGF and
myogenic systems or possibly the third mechanism. Multiple studies indicate that the myogenic mechanism of normal
rats and SHR generates spontaneous oscillations of 0.1– 0.3
Hz, whereas MD-TGF produces oscillations of ⬃0.035 Hz
(289, 297, 628, 629, 631). However, the oscillations were
more irregular in rats with spontaneous or renovascular
hypertension (230, 625). Step changes in RPP elicited vascular oscillations at two frequencies corresponding to the
myogenic and MD-TGF responses (631).
5. Relative contributions of the different mechanisms
Most in vivo studies reported a ⬃40 –55% contribution of
myogenic and 25–35% contribution of MD-TGF responses
to dynamic autoregulation in dog, mouse, and rat kidneys
to a sudden, step increase in RPP (286, 748 –751, 753, 756).
Aside from frequency analysis of admittance gain, the individual components have been studied only after selective
blockade of MD-TGF, since prevention of the myogenic
response, for example, by blockade of VOCCs, abolished
vascular responses to all autoregulatory mechanisms (749,
1064). Blockade of MD reabsorption with loop diuretics
partially impairs overall renal autoregulation in kidneys of
dogs (749, 760, 1622), rats (749 –751, 1626), and mice
(668).
Clausen and Aukland, using a previously described box
technique (1601), placed a rat kidney in an airtight chamber
and acutely reduced the atmospheric pressure of the chamber by 35 mmHg. This reduced RIHP and increased vascular transmural pressure in this case by stretching the vessel
from outside. These authors observed a rapid, robust renal
vasoconstriction that was unaffected by blockade of MDTGF by furosemide (265). They concluded that the myogenic vasoconstriction is much stronger than that induced
by MD-TGF.
The MD-TGF component of renal autoregulation can be
abolished by ureteral obstruction (297), furosemide (19,
631, 749, 754, 1358), or genetic deletion of adenosine A1
receptors (751). As expected, all TGF components were
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CARLSTRÖM ET AL.
absent from the admittance pattern in the HNK preparation
lacking tubules, but the myogenic mechanism at 0.1– 0.3 Hz
persisted in all of these conditions and generally became
stronger and faster in the absence of MD-TGF (287, 1358),
as might be expected in the absence of MD-derived NO (see
sect. VIC). Overall, the myogenic mechanism appears to be
dominant in that it is essential and sufficient for efficient
RBF autoregulation. MD-TGF tends to provide a secondary
or back-up system to enhance total efficiency when the
myogenic mechanism is attenuated.
One study of frequency analysis concluded that an increase
in RPP increased the strength of both the myogenic and
MD-TGF mechanisms (1636). The efficacy of the myogenic
mechanism varies over time after a change in PP (247, 875).
There are additional actions of furosemide besides inhibition of NKCC2 transport in MD cells that may contribute
to its effects on renal autoregulation. Furosemide has a
direct vasorelaxant action in isolated, preconstricted afferent arterioles of mice by blockade of the NKCC1 transporter (1124). Indeed, inhibition of this transporter in the
afferent arteriole of the HNK preparation lacking MD-TGF
attenuated ⬃70% of myogenic response to changes in RPP
(1568). The natriuresis following blockade of tubular NaCl
reabsorption with furosemide increased the PPT (170, 749,
1124), which might attenuate the afferent arteriolar myogenic response if the transmural pressure was reduced, although RIHP was reportedly unchanged (789). On the
other hand, swollen tubules could compress peritubular
capillaries to increase vascular resistance and reduce RBF
(1124). Nevertheless, in one study a furosemide diuresis did
not change SNGBF, although RIHP was increased (1489).
Thus reduced autoregulation after furosemide may not necessarily indicate an exclusive contribution of MD-TGF. In
other studies, furosemide reduced RBF or GFR in intact
kidneys (1124), but the mechanism was not clear. Thus
furosemide may increase or decrease RBF and GFR by
mechanisms that have little to do with inhibition of MDTGF.
In summary, the myogenic response normally contributes
⬃50%, MD-TGF ⬃35%, and the third mechanism ⬃10 –
20% to dynamic renal autoregulation following a step increase in RPP (FIGURE 3B). Frequency analysis admittance
gain suggests less effective overall autoregulation with a
rather stronger contribution of the myogenic (⬃65%) than
the MD-TGF mechanism (⬃35%) (FIGURE 3C). The myogenic response contributes ⬃65% and MD-TGF ⬃35% at
high RPP in the JMN preparation (FIGURE 3D). There are
variable interactions between myogenic and MD-TGF
mechanisms, as discussed in section IIC.
B. In Vitro Studies in Isolated Preparations
The myogenic response has been studied from videometric
measurements of the diameter of afferent arterioles in re-
sponse to changes in RPP in the JMN preparation after
inactivation of MD-TGF (FIGURE 3D) or in the HNK preparation lacking tubules and thus devoid of any MD-TGF or
CT-GF (FIGURE 3E). Moreover, use of single isolated, perfused afferent arterioles allows calculation of the slope of
the regression of active wall tension on PP, which provides
a quantitative measure of the myogenic response throughout the PP range studied (FIGURE 3F). The intercept of this
regression on the x-axis indicates the threshold for initiating
a myogenic response. Myogenic and MD-TGF mechanisms
also have been studied using the isolated double-perfused
JGA preparation (702, 703).
1. The isolated JGA
Bell and associates (801) developed a rabbit nephrovascular
unit in which a glomerulus was attached to its MD segment
that was perfused via the TAL to characterize epithelial
transport properties. Early studies of renin release from the
JGC of the microdissected afferent arteriole were performed with the glomerulus attached or absent (698, 1377).
Mechanisms regulating renin release for JGC were also investigated in the HNK preparation (162, 163). Subsequent
studies demonstrated pressure-dependent renin secretion
from a perfused rabbit afferent arteriole with parent glomerulus present (122, 1181). In 1987, Skott and Briggs
(1378) used the isolated JGA to show that luminal NaCl
concentrations influenced MD signaling that regulated
renin secretion from JGC. Shortly thereafter, Ito and Carretero (702, 703) characterized the myogenic and MD-TGF
responses in a rabbit JGA preparation that was doubleperfused via the MD and the afferent arteriole. Activation
of MD reabsorption by increasing tubular [NaCl] constricted the afferent arteriole adjacent to the glomerulus,
whereas a pressure-induced myogenic constriction occurred
in more proximal segments of the afferent arteriole. This
preparation has been used commonly to characterize MD
metabolites that modulate the strength of afferent arteriolar
responses to MD-TGF signaling. Examples include potentiation by ATP, adenosine, O2⫺ (913, 1217), and attenuation by NO and CO (702, 1225, 1226). Recent studies in
the mouse isolated JGA indicated that MD cells can detect
variations in tubular fluid flow, independent of the salt
composition, by activation of primary cilia on MD cells,
which subsequently increases [Ca2⫹]i in afferent arteriolar
VSMCs and causes vasoconstriction (1374).
2. The isolated connecting tubule and glomerular/
afferent arteriolar unit
A variation of the isolated JGA is a tubulovascular unit
consisting of an individual CT and attached afferent arteriole and glomerulus (822, 1035, 1230). Many CTs, especially in the outer cortex, return to their parent glomerulus
and attached afferent arteriole (339, 1538). Three-dimensional tracing of 168 nephrons indicated that the terminal
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RENAL AUTOREGULATORY MECHANISMS
portion of the distal convoluted tubule contacted the afferent arteriole of the parent glomerulus in 90% of shortlooped and 75% of long-looped nephrons of the mouse
kidney (1215). Such findings reaffirmed previous observations of 100% contacts in superficial nephrons and 60% of
midcortical nephrons of the rat kidney (339). Earlier serial
sections of 60 nephrons revealed that the late distal tubule
came within 3 ␮m of the afferent arteriole in 90% of superficial glomeruli, 87% from midcortical glomeruli, and 73%
of juxtamedullary glomeruli (67).
Carretero and associates have conducted a series of in vitro
and in vivo studies establishing the functional implications
of CT-GF regulation of afferent arteriolar vasomotor tone.
Tubular flow-dependent reabsorption of Na⫹ by the rabbit
or rat CT was mediated primarily by the amiloride/benzamil-sensitive ENaC (1230). Increased Na⫹ reabsorption
promoted epithelial cell production of PGE2 by COX-1 and
an EET by a cytochrome P-450 epoxygenase (1219, 1221),
both of which dilate the afferent arteriole. PGE2 induced
endothelium-independent dilatation via activation of the
EP4 receptor (1223). Earlier immunolabeling studies of
principal cells that express ENaC suggested colocalization
of membrane-associated PGE synthase with COX-1 but not
COX-2 (176, 1539). In contrast, COX-2 but not COX-1
was expressed in MD cells in both rats and mice. COX-2
was also expressed in the intra- and extraglomerular mesangium.
Tubular ANG II enhanced CT-GF, probably by simulating
Na⫹ reabsorption in the CT (1219). The effect of ANG II on
CT-GF was mediated via a protein kinase C (PKC)/NOX2/O2⫺ pathway (1227). In contrast to the conventional MDTGF, this suggests a vasodilator component to ANG II action due to CT-GF. Moreover, inhibition of tubular NOS
paradoxically increased the vasodilation induced by CTGF, suggesting that NO is not a mediator of the vasodilation but that NO rather inhibits Na⫹ reabsorption in CT,
thereby preventing the generation of the signal for the vasodilator response (1230). In vivo micropuncture studies
showed that increased tubular NaCl delivery activated the
CT-GF circuit to reduce the estimated PGC and offset the
MD-TGF-mediated constriction of the preglomerular vasculature (1558). CT-GF contributed also to acute resetting
of MD-TGF during changes in ECV and Na⫹ excretion
(1554). Such vasodilation and resetting were more pronounced in Dahl SS than in SHR rats consuming a high-salt
diet, thereby leading to increased PGC in the Dahl SS rats
(1555). In the absence of the MD-TGF circuit, activation of
CT-GF in vitro blunts the magnitude of the PP-induced
myogenic contraction of the afferent arteriole (Carretero
and associates, personal communication).
3. The juxtamedullary nephrovascular unit
Casellas and Navar (202) developed an in vitro JMN preparation perfused with low hematocrit blood or an albumin
424
solution to study the microvascular reactivity and the MDTGF of deep cortical nephrons. A rat kidney was sectioned
longitudinally and the papilla reflected to expose the overlying pelvic mucosa on the inner surface of the cortex where
the glomerular arterioles were visualized directly. Increased
RPP reduces the luminal diameters of the cortical radial
artery and afferent arteriole, but the diameter of the efferent
arteriole is unchanged or even increased (193, 199 –201,
580, 611, 1281, 1395, 1437). This preparation allows separation of the myogenic response from the MD-TGF without the potential complication attendant on the use of loop
diuretics by preventing MD perfusion by a tubular oil block
or papillectomy (200, 202, 686, 1020, 1281, 1395, 1437).
A doubling of RPP reduced afferent arteriolar diameter by
15–30% (1020, 1437), which was sufficient to yield nearperfect autoregulation of blood flow since resistance to flow
is a fourth power relation to the radius of the vessel. The
reduction in luminal diameter was limited to 7–10% after
elimination of MD-TGF by papillectomy, oil blockade to
halt tubular flow, or furosemide (FIGURE 3D) (1020, 1437).
Abolition of an active response with a Ca2⫹-free solution
increased arteriolar diameter by 20% when RPP was doubled (1020, 1437). Thus the modest reduction in arteriolar
diameter during a doubling of RPP after blockade of MDTGF still represents a considerable increase in vascular
tone. Afferent arteriolar autoregulatory constriction following increased RPP from 60 to 140 mmHg was attenuated by ⬃35% by blockade of MD-TGF, indicating the
myogenic mechanism accounts for ⬃65% (FIGURE 3D).
Both mechanisms were abolished by blockade of VOCCs
with nimodipine.
Measurements of hydrostatic pressures along the preglomerular vasculature during increased RPP indicated that
20% of the increase in resistance occured before the end of
the cortical radial artery, 65% by the end of the afferent
arteriole, and 80% along the composite preglomerular vascular tree (201). The terminal glomerular segment of the
afferent arteriole was twice as responsive as the upstream
segments (200, 1020, 1437). Afferent arteriolar blood flow
remained constant during changes in RPP above 95 mmHg
(580, 1437). Increasing RPP from 80 to 120 to 180 mmHg
increased PGC only modestly from 45 to 50 to 53 mmHg,
respectively (1281). Similar studies reported a 0.10- to
0.19-mmHg change in PGC per mmHg change in RPP
within the autoregulatory range (193, 201). Thus this preparation retains excellent autoregulation of nephron flow
and PGC within the physiological range.
4. The isolated perfused afferent arteriole
Edwards (375) developed a rabbit isolated, perfused renal
arteriolar preparation in 1983 to study the myogenic response and reactivity to vasoactive agents. Initial studies
reported maintenance of luminal diameter of cortical radial
arteries and afferent arterioles or constriction up to 11% to
increased PP compared with dilation of efferent arterioles
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CARLSTRÖM ET AL.
(375). Thereafter, the myogenic response was characterized
in isolated preglomerular vessels from dogs (562, 777,
1059), rabbits (697, 747), rats (700, 1224, 1637), and more
recently from mice (462, 728, 729, 861, 864, 866). A doubling of PP led to an 11% reduction in diameter of mouse
afferent arterioles that was complete within 5 s due to a
linear increase in active wall tension as a function of PP
(FIGURE 3F) (861). While this preparation excludes nonvascular paracrine factors, it requires an artificial perfusate free
of erythrocytes. Moreover, it is technically challenging to
measure the precise PP at the tip of the perfusion pipette.
Myogenic contraction, assessed as active wall tension, is
determined as the difference between the tension in physiological versus Ca2⫹-free EGTA-containing solutions.
Myogenic contraction was associated with increased
VSMC [Ca2⫹]i and increased ROS measured by fluorometric markers (864, 1224). The slope of the calculated regression of active wall tension on PP quantifies the myogenic
response with the intercept on the x-axis defining the
threshold PP for initiating a response (FIGURE 3F). The
threshold pressure was 35– 40 mmHg for the mouse isolated afferent arteriole (861, 864), 60 – 80 mmHg for the
preglomerular vasculature of the rat (700, 1637) and rabbit
(747), and 80 mmHg for the dog (562, 1059). The estimated or directly measured PGC in the euvolemic rat averaged 55 mmHg (42, 47, 58, 74, 87, 118, 199, 320, 334,
416, 1008, 1488) and was calculated to be similar in the
mouse (861). PGC was estimated to be 60 –70 mmHg in the
dog kidney (86, 1068, 1070, 1073, 1138, 1139) and 31
mmHg in the anesthetized rabbit (323). Thus these data
suggest that myogenic responses generally start at PPs below ambient levels of PGC, except in the rabbit, and may
thereby contribute to both dilation of the afferent arteriole
during reductions in RPP and constriction during increases
in PP.
5. The HNK
Steinhausen and associates (1413, 1415) developed the atubular, postischemic HNK preparation to facilitate direct
visualization of the renal cortical microcirculation and
glomeruli. This preparation allows intravital microscopic
measurements of vessel diameter and erythrocyte velocity in
an exclusive vascular preparation perfused with blood or
artificial solutions. During the development of hydronephrosis, the kidney parenchyma becomes progressively
thinner due to tubular atrophy, resulting in a tissue sheet of
cortical vessels of ⬃200 ␮m thick. Approximately 6 – 8 wk
after unilateral ureteral obstruction, there was complete
tubular atrophy (162, 1415). This preparation has been
used to investigate mechanisms of renin release and electrophysiological characteristics of JGC of the afferent arteriole
(162, 164). In addition to being readily amenable to study
of electrophysiology of the renal microcirculation, the
HNK provides an opportunity to investigate the myogenic
response of various segments of the preglomerular vasculature in the absence of input from either MD-TGF or CT-GF.
Videometric measurements were made of the diameter of
renal arterioles during perfusion in situ with blood or in
vitro with an artificial saline solution (1413, 1415). Loutzenhiser and associates (586) have used the HNK extensively to characterize the myogenic response in the absence
of any TGF. Increased RPP contracted cortical radial arteries and afferent arterioles but not efferent arterioles (FIGURE
3E) (586). Furthermore, frequency domain analysis reported a relatively well-maintained myogenic mechanism
with a threshold for activation of 60 mmHg (287) and
preglomerular vasoconstriction of 7–23% with a doubling
of RPP (586) that was complete within 5–10 s (802, 927,
931). The EM of cortical radial arterial and afferent arteriolar VSMCs averaged ⫺40 mV at 80 mmHg, which was
just below the threshold required to initiate a myogenic
response (928). Overall, RBF autoregulation in this preparation, which lacks MD-TGF, was weak when perfused
with a salt solution devoid of colloid or erythrocytes. This
was apparent from a steady-state AI of ⬃0.85 over the RPP
range of 60 –140 mmHg and a dynamic autoregulatory
fractional admittance gain of only ⬃0.8 in the PP range of
100 –140 mmHg (287). These values are considerably
higher than the same determinations in efficiently autoregulating intact kidneys during inhibition of MD-TGF (287,
297, 749, 753, 760). The HNK preparation suffers from
some other limitations including the low viscosity of a cellfree perfusion solution which influences normal NO production and precludes its uptake into oxyhemoglobin. Nevertheless, the preparation responded well to ACh-induced
NO release (1486).
C. Interactions Between MD-TGF and the
Myogenic Mechanisms
Interactions between the myogenic and MD-TGF mechanisms provide renal autoregulation with unique opportunities to regulate preglomerular vascular tone (200, 231, 245,
285, 625). The most distal portion of the afferent arteriole
was the major effector site for both the myogenic and the
MD-TGF responses (200). Studies have demonstrated positive, negative, or absent interactions between these two
mechanisms. The participation of a glomerular feedback
includes both the conventional MD-TGF and the more recently described CT-GF. It is firmly established that the
MD-TGF influences the myogenic response, which in turn
impacts the MD-TGF (244 –246, 630, 1163, 1205, 1341,
1401, 1402, 1547).
Interactions between the oscillating frequencies of the myogenic and the MD-TGF mechanisms have been observed in
whole kidney blood flow and single-nephron studies. Early
studies of myogenic fluctuations in SNGBF in the superficial
cortex revealed large amplitude oscillations at 0.1– 0.2 Hz
in response to inhibition of MD-TGF with furosemide,
whereas the myogenic oscillations were strongly damped
when MD-TGF was stimulated maximally by tubular per-
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425
RENAL AUTOREGULATORY MECHANISMS
fusion (1636). This suggested that MD-TGF tonically inhibits the amplitude of intrinsic vascular tone driven by the
myogenic mechanism. Also inhibited were MD-TGF-dependent communications with adjacent afferent arterioles
and glomeruli (626). Recent wavelet analysis of blood flow
and tubular pressure confirmed that MD-TGF modulated
the frequency and amplitude of oscillations initiated by
myogenic mechanisms (1400). These dynamic interactions
occur within and between nephrons and are nonlinear and
time-varying (405, 630, 973, 975). Conversely, delivery of
the tubular fluid to the MD and the CT is altered by the
myogenic mechanism and thereby modulates TGF responses. Such coupling has been modeled extensively with
descriptions of nonlinear modulation of the amplitude and
frequency of myogenic oscillations by MD-TGF (244, 245,
395, 875, 973, 973, 975, 976, 1205, 1258, 1400). These
interactions appeared to vary between cortical and medullary nephrons (974) and may contribute to fluctuations in
the RPP set-point for RBF autoregulation (1172). The interactions were more variable in SHR than in SD rats (247,
626). Based on simulation studies (395), Holstein-Rathlou
and associates concluded that the myogenic response needs
to be active to have a MD-TGF mechanism participate in
RBF autoregulation. Indeed, there are examples when MDTGF is present and yet RBF autoregulation is very weak to
absent.
However, studies using frequency domain analysis have
concluded that autoregulatory responses in one afferent arteriole can generate both positive and negative interactions
with others (231, 245, 246, 628). MD-TGF can modulate
both the frequency and amplitude of oscillations arising
from the myogenic mechanism. Most nephrons in normotensive rats originating from a common renal cortical radial
artery had highly regular periodic synchronization of MDTGF and myogenic modes. However, the interactions in
SHR were more complex with transient, irregular coupling
and synchronization (231, 875, 1205, 1401). Also, the lowfrequency (0.01 Hz) oscillatory component of renal autoregulation, perhaps representing the third component,
modulateed both the myogenic response and MD-TGF activity (1163, 1341, 1375), with weaker interactions in SHR
than in SD rats (1375).
In vivo micropuncture studies by Schnermann and Briggs
(1308) reported that the maximum MD-TGF-mediated reduction in the estimated PGC was 13 mmHg when RPP was
120 mmHg, but was reduced to 3 mmHg when RPP was
lowered to 80 mmHg. Thus the magnitude MD-TGF increased in parallel with RPP, and effective autoregulation of
the estimated PGC was strongly dependent on tubular flow
past the MD. These results demonstrate two-way positive
interactions between myogenic and MD-TGF mechanisms
in vivo. The MD-TGF response is required for a full myogenic response, and conversely, the degree of myogenic contraction regulates the reactivity of MD-TGF.
426
Recent studies have provided further evidence of a positive
reinforcement between the MD-TGF and myogenic mechanisms. Dynamic studies using frequency analysis in the rat
found that MD-TGF inhibition with furosemide attenuated
characteristics associated with myogenic reactivity (reducing the slope of gain reduction and the associated phase
peak) (1358), suggesting removal of positive MD-TGF
modulation of the myogenic mechanism. In the conscious
mouse, furosemide eliminated the frequency domain signature of MD-TGF and reduced the shoulder operating frequency of the myogenic mechanism (from 0.3 to 0.2 Hz),
indicative of a slowing of the myogenic response (668).
Dynamic studies by Walker and Navar (1547) on the rat
JMN preparation in the time domain revealed a positive
interaction between MD-TGF and the myogenic response
of afferent arterioles. A rapid step increase in RPP produced
a prompt but relatively short-lived (⬃13 s) monotonic myogenic vasoconstriction of the afferent arteriole when MDTGF was inactivated by papillectomy, whereas there was a
biphasic contractile response with the initial myogenic response lasting ⬃24 s when MD-TGF was intact, indicating
positive interaction between these two mechanisms (1547).
With MD-TGF operational, a biphasic response included a
decline in afferent arteriolar diameter after 24 s, albeit at a
slower rate, to reach a 26% reduction at 93 s. The initial
myogenic response had a time constant of 6 –11 s (0.16 –
0.09 Hz), whereas that of MD-TGF was 37 s (0.027 Hz).
The delay in the initiation of the myogenic response was 6 s,
and the rate of myogenic contraction was the same whether
MD-TGF was engaged or inoperative. There was no evidence for a very slow third mechanism in this study. Autoregulation of the in vitro JMN preparation was stronger in
the initial but not the sustained phase after MD-TGF was
activated by increasing NaCl delivery to the MD (662). It is
noteworthy that inhibition of MD-TGF with furosemide
did not affect the myogenic response in vivo after NOS was
inhibited (749, 750), a finding consistent with an action of
furosemide to inhibit MD-TGF and NO generation and
modulation of myogenic tone.
However, several studies suggested weak to no interaction
between MD-TGF and the myogenic mechanism. Transfer
function analysis revealed that furosemide inhibited the
MD-TGF signature at 0.03– 0.05 Hz with a weak effect of
the myogenic response between 0.1– 0.2 Hz in the rat, reducing the gain at frequencies below 0.15 without changing
the peak of the phase angle (19). Similar inhibition of MDTGF had little effect on the myogenic response in the dog
(760) or mouse (299), but furosemide paradoxically augmented the myogenic response in adenosine A1 receptor
deficient mice lacking MD-TGF (751). However, inhibition
of MD-TGF by ureteral obstruction in the rat abolished the
MD-TGF signature of admittance gain without affecting
dynamic features of the myogenic response (297). Consistent with a lack of effect of MD-TGF on myogenic respon-
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CARLSTRÖM ET AL.
siveness, activation of MD-TGF by inhibition of proximal
NaCl reabsorption by acetazolamide to increase MD delivery of NaCl had little influence on the myogenic mechanism
in vitro (662) or in vivo (749). An increased myogenic tone
elicited by reducing perirenal pressure in the isolated perfused rat kidney was unaffected by MD-TGF inhibition
with furosemide (265). Thus myogenic vasoconstriction
can function independently from MD-TGF.
RVR responses to a sudden, step increase in RPP gave the
impression that the initial myogenic response was enhanced
during inhibition of MD-TGF with furosemide, increasing
its participation in the first 10 s from 40 to 60% of the total
response in the dog (751, 753) and from 40 to 55% of total
efficiency with an enhanced response rate in the rat (749,
750). However, the appearance of coupling between MDTGF and myogenic mechanisms depends crucially on the
protocol used and the operational status of MD-TGF while
RBF is normal and PP is varied within the autoregulatory
range. During frequency analysis to generate a transfer
function of admittance gain, spontaneous or forced oscillations of RPP continually change tubular flow past MD cells
to modulate MD-TGF activity in positive and negative directions. In contrast, analysis based on a sudden step change
in RPP usually starts with a reduced PP and diminished
tubular flow and MD-TGF activity. The resultant vasodilation tends to offset or counter the stimulus for rapid myogenic vasoconstriction when RPP increases. This may explain the increased strength and speed of the myogenic response observed following a rapid increase in RPP when
MD-TGF is inhibited since the opposing preexisting vasodilator input to arterial tone is removed. This spurious result is less evident during inhibition of the more symmetrical
activity of MD-TGF during frequency analysis of admittance gain. Inhibition of MD-TGF by acute volume expansion tends to increase the contribution of the myogenic
mechanism (from ⬃33 to 50%) of total autoregulatory adjustments in RVR to a sudden step increase in RPP in the
wild-type mouse (462, 505). Again, this could be explained
by removing the restraining effect of preexisting MD-TGFinduced vasodilation at low tubular flow on the initial myogenic vasoconstriction following the increase in RPP. Total
steady-state autoregulatory efficiency was unaffected by
such inhibition of MD-TGF. Collectively, these results suggest that the myogenic mechanism is more designed to protect against increases in BP and that the MD-TGF negativefeedback system is more supportive of RBF and GFR during
reductions in BP.
Furosemide might cause some renal vasodilation by increasing NaCl delivery to the CT and stimulating CT-GF. Afferent arteriolar vasodilation mediated by CT-GF attenuated
the strength of vasoconstriction by MD-TGF and myogenic
mechanisms (1554, 1555, 1558) (O. A. Carretero, personal
communication). However, furosemide had little effect on
the contribution of the putative third mechanism in either
the dog or rat (749, 753), although it was abolished by
furosemide in a mouse study (751). Furosemide may also
impact autoregulation by inhibiting Na⫹-K⫹-2Cl⫺ transport in VSMC to affect preglomerular vascular tone (522,
835, 1124, 1568). Effects of loop diuretics on NKCC1
transport by VSMC and their impact on myogenic tone of
the afferent arteriole in vitro are discussed in section IVA.
Four mechanisms have been proposed to account for observed positive interactions between the MD-TGF and the
myogenic responses. First, a MD-TGF-induced constriction
of the terminal afferent arteriole should increase the upstream intravascular pressure and thereby enhance the signal for a myogenic contraction in more proximal afferent
arteriolar segments (200, 1021). Second, MD-TGF triggered a Ca2⫹ wave that spread from the MD throughout the
JGA to the parent afferent arteriole that could enhance
myogenic responsiveness (1176). Third, membrane depolarization of the afferent arteriole by an active MD-TGF
should enhance Ca2⫹ entry through VOCCs and thereby
myogenic contractions. Fourth, MD-TGF-induced depolarization of the afferent arteriolar VSMCs can be transmitted
upstream (976, 1176) to constrict neighboring afferent arterioles stemming from the same cortical radial artery (231,
762). Electrical stimulation of the distal afferent arteriole
initiated electrical and Ca2⫹ entry responses that were conducted upstream along the afferent arteriole (527) and cortical radial artery (1279), presumably mediated by gap
junctions (527). Depolarizing current caused vasoconstriction and hyperpolarizing current caused vasodilation
(1414). High KCl-induced depolarization also elicited a
constrictor response of upstream arterioles and neighboring
afferent arterioles, with a long mechanical length constant
of ⬃325 ␮m (1279, 1544). The strength of internephron
coupling was greater in SHR than in SD rats (1544). Such
coupling could account for synchronized MD-TGF-mediated contractions in pairs or triplets of nephrons (630).
MD-TGF initiated stronger interactions with afferent arterioles originating from a common cortical radial artery in
SHR than in SD rats (231).
The molecular mechanisms by which MD-TGF interacts
with the myogenic mechanism are not certain. Positive interactions may reflect vasoconstrictor signaling Ca2⫹ pathways or perhaps involving ATP and P2X1 receptors or adenosine and A1 receptors, as discussed in section IIA3, A and B.
Alternatively, as is discussed in section VIB, NO generated
by neuronal NOS in MD cells during activation of MDTGF could account for a negative interaction since endogenous NO markedly inhibits both the strength and the
speed of the myogenic response.
In summary, it is clear that there are communications and
interactions among vascular and tubular mechanisms mediating autoregulation in the kidney, but their physiological
significance remains elusive. Both reinforcing and opposing
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RENAL AUTOREGULATORY MECHANISMS
interactions between myogenic and MD-TGF mechanisms
have been reported. This may relate to coupling based on
the balance of positive and negative modulators of vasomotor tone of afferent arterioles, which can be generated by
activated MD or CT cells, as summarized in FIGURE 6 and
discussed in more detail in section VI. The complexity is
increased further by the fact that the degree of information
transfer can vary in a nonlinear manner over time and MDTGF may contribute intermittently to autoregulation. The
cellular events and consequences of interactions between
MD-TGF as well as CT-GF mechanisms and the myogenic
response are poorly understood, but modulation of NO and
Ca2⫹ signaling appear to be involved. As is discussed in
section VIC, NO modulates the renal myogenic response
and interactions between tubular and vascular mechanisms,
but the primary source is still controversial.
D. Kinetics of the Myogenic Response
Both the magnitude and the kinetics of the myogenic response vary among different circulatory beds. There is a
tendency for the speed of the myogenic response to be greatest in the smallest diameter arterioles. The renal vasculature
has the fastest and most complete response, followed by the
cerebral and then mesenteric arterioles.
The myogenic response of renal afferent arterioles of mice,
rats, and dogs (internal ID: 8 –20 ␮m) is often complete
within 5–10 s, whereas in other vascular beds it ranges from
⬃10 –15 s for small cremaster muscle arterioles (15–25 ␮m)
(613, 613, 615) to 60 –120 s for larger mesenteric and cremaster arterioles (⬃100 ␮m) (303, 740, 1671) and up to 5
min for mesenteric arteries and skeletal muscle arterioles
(⬎180 ␮m) (243, 667, 1002). This diversity is probably
related to a specific set of VSMC mechanosensation-contraction signaling systems. Whereas the depolarization and
Ca2⫹ entry through VOCCs are ubiquitous, distinct upstream signaling systems appear to provide tissue-specific
mechanisms of adaptation to local metabolic needs involving the supply of oxygen and fuels that are triggered by
changes in BP.
The myogenic response in the renal microcirculation is engaged within 1 s and is complete in ⬍5–10 s in intact rodent
kidneys (265, 462, 505, 749 –751, 756, 1640), mouse isolated afferent arterioles (861) or rabbit (747), or rat afferent
arteriole of the JMN (1547) or the HNK preparation (927).
This time frame corresponds closely to the 0.1– 0.3 Hz frequency band for the myogenic admittance transfer function
(FIGURE 3C) (109, 289, 297, 629, 749). Slower responses of
40 s were reported in one study of rat pressurized JMN
arterioles (1637) and of 60 –120 s in hamster preglomerular
arterioles transplanted to the cheek pouch (473).
As already discussed in the previous section, Walker and
Navar (1547) detected two components in the autoregula-
428
tory contractile response to a single step increase in PP of
the JMN preparation. The prolonged delay (⬃6 s) in the
initiation of the myogenic response reported in those studies
of the JMN preparation may reflect methodological problems, since much more rapid responses have been reported
in other studies among isolated afferent arterioles or in the
HNK preparation.
Loutzenhiser et al. (927) used the rat HNK preparation to
characterize the kinetics of the myogenic response in the
absence of any tubular influence. The vasoconstrictor response to an 80-mmHg rise in RPP was a monotonic contraction after a delay of ⬃0.3 s, with a time constant of 4 s.
The onset of the myogenic response of the HNK, based on
changes in arteriolar wall diameter, was very rapid and
averaged ⬃0.30 – 0.35 Hz, which is considerably faster than
values reported in vivo. A possible contributor to this unusually rapid response is the use of a low viscosity, colloid,
and RBC-free saline perfusion solution as well as the lack of
tubular modulatory agents. The vasodilator response to an
80 mmHg reduction in RPP was slower and more complex.
After a delay of 1 s, the response was biexponential with
time constants of 1 and 14 s, requiring almost 25 s for
complete relaxation. Based on those results, the authors
concluded that rapid pulsations should evoke sustained vasoconstriction due to the faster contraction when RPP rose
compared with the more sluggish vasodilatation when PP
fell. Consistent with this prediction, the magnitude of afferent arteriolar contraction in the HNK preparation was related to the peak systolic pressure for PP oscillations between 1 and 6 Hz. These investigators proposed that the
primary function of the myogenic response at the normal
heart rate frequency is to protect glomerular capillaries
from the damaging effects of the systolic BP rather than to
maintain a constant GFR to regulate body fluid homeostasis
(933, 934).
In contrast to these results for the HNK preparation, most
whole kidney studies of frequency domain analysis of renal
vascular admittance have reported a frequency for the myogenic response of 0.20 – 0.25 Hz (FIGURE 3C), as discussed
earlier in section IIA5. Moreover, Just and Arendshorst
(749, 751) reported that intact kidneys had a similar rate of
myogenic contraction and relaxation to a 20-mmHg step
change in RPP. Both responses were complete within 8 s
(749, 751). The myogenic contraction to an increase in RPP
in intact kidneys occurred slightly earlier, with a shorter
delay time (0.39 vs. 0.53 s) and contributed a smaller fraction of total autoregulation of ⬍37% compared with the
myogenic relaxation to a decreased RPP which was ⬍52%
(750). Moreover, the time for complete contraction of 5.1 s
was longer than for complete relaxation of 2.6 s. Accordingly, the in vivo renal myogenic response buffered increased and decreased RPP similarly and thus should respond primarily to the mean RPP, rather than preferentially
to the systolic BP. Support for this conclusion comes from
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CARLSTRÖM ET AL.
earlier studies that failed to detect an influence of arterial
pulse pressure on RBF autoregulation (1238, 1344). The
observed dynamic values for autoregulation in the studies
of Just and Arendshorst (750) were likely underestimates
since the in vivo changes in RPP, although abrupt, were not
instantaneous.
strictors, e.g., ANG II or AVP, to increase RPP had no
major effect on the renal myogenic response (750, 1193,
1563). The rate of change in RPP is another factor that may
modulate renal autoregulatory responses. During stepwise
increases in RPP in conscious rats, larger changes in RVR
were associated with more rapid changes in PP (423).
These striking differences reported for the myogenic contraction between the in vitro atubular HNK and in vivo
intact kidney preparations may relate to the presence of
active tubular cells only in the latter, since MD metabolites
impact on VSMC kinetics. Specifically, NO production affects the myogenic mechanism, as discussed in section VIC.
Moreover, activation of MD cells can accelerate the rate of
relaxation associated with the generation of PGE2 (218,
1036, 1334) and NO (298, 1036). Indeed, Loutzenhiser et
al. demonstrated later that adding exogenous NO or cGMP
to the HNK preparation to more closely simulate the in vivo
paracrine modulation, preferentially reduced the delay in
the vasodilation response to a reduced RPP (R. Loutzenhiser, personal communication), thereby reducing the time
difference between myogenic relaxation and constriction
which more closely approximated to those observed in vivo.
The myogenic response appears to be somewhat faster in
conscious than in anesthetized animals. Studies by Cupples,
Bidani, Griffin and colleagues reported the resonance frequency of the myogenic mechanism to be 0.23– 0.25 Hz in
conscious rats (886, 1193), compared with the general finding of 0.18 – 0.21 Hz in rats anesthesized with isofluorane
or barbiturates (109, 297, 499, 597, 749, 1274, 1358,
1569, 1570, 1572). There were similar responses during
anesthesia with thiobutabarbital (597, 1274) and pentobarbital (297, 749), but halothane slowed the operating frequency of the myogenic mechanism in SD, SHR, and WKY
rats to 0.10 – 0.15 Hz (230, 289, 631, 886, 1636).
The resonance peak in admittance gain of dynamic autoregulation is an index of the natural frequency of the system
(628). The dynamic autoregulation of arterial blood flow in
euvolemic Wistar and SHR rats was excellent in the renal
and in the superior mesenteric circulation, although the
myogenic response was faster (0.22 Hz) in the denervated
kidney than in the denervated gut (0.13 Hz) (7). This was
confirmed in two other studies (886, 1572). In contrast,
blood flow to the hindquarters lacks any dynamic autoregulatory signature.
Cupples and associates (1572) reported that the range of
RPP tested in the HNK preparation perfused with artificial
medium determined the speed of the myogenic response
assessed as transfer function admittance gain. Thus an increase in mean RPP from 80 to 140 mmHg increased the
myogenic operating frequency from ⬃0.265 to 0.37 Hz. In
a similar in vivo study in Wistar rats, inhibition of NOS
with L-NAME increased the RPP from 115 to 140 mmHg
and increased the myogenic resonance frequency from 0.21
to 0.25 Hz. This change was attributed primarily to PP since
it was prevented by maintaining PP by aortic clamping during NOS inhibition. This pressure sensitivity was unique to
the kidney as the myogenic resonance frequency in the mesenteric circulation (0.15– 0.16 Hz) was unaffected by LNAME hypertension. In another study by the same laboratory, however, hypertension (115–145 mmHg) induced by
L-NAME was reported to increase the strength of the myogenic response (both the slope and the amplitude of admittance gain in the 0.1– 0.2 Hz window) without affecting its
speed; the myogenic resonance frequency was unchanged at
0.18 – 0.20 Hz (1569). Other studies employing vasocon-
Neurohormonal and paracrine agent also modulate the
speed and strength of the myogenic response, as exemplified
by the effect of NO, discussed earlier and first reported by P.
Persson and associates (1626). ANG II is reported to augment the myogenic resonance peak from 0.23 to 0.27 Hz in
rats and increases the fractional gain by 25% and the slope
of the reduction in gain, whereas phenylephrine (PE) decreases fractional gain by 30% and the slope of the gain
reduction without affecting the resonance peak (0.24 – 0.25
Hz). PE had little effect on MD-TGF (1193). The myogenic
resonance peak also was increased by ANG II in conscious
dogs (755). As is discussed in section VIC, NOS inhibition
in the intact kidney markedly accelerates and magnifies the
myogenic mechanism.
Expression of different isoforms of smooth muscle myosin
heavy chain (MHC) has been proposed to explain the more
rapid contraction of the afferent arteriole compared with
the efferent arteriole. The B-isoform of MHC inserts into
the ATP binding pocket to activate VSMC contraction. The
afferent arteriole expressed predominantly the rapidly recycling MHC-B isoform, whereas the efferent arteriole expressed only the slower-cycling, alternatively 5’-spliced
MHC-A isoform (1161, 1361). However, the rate of afferent arteriolar contraction was unaltered in mice with a mutated form of MHC-B (1161). Thus variable expression of
VSMC MHC isoforms could not explain the differential
speed of contraction of afferent and efferent arterioles.
In summary, myogenic tone changes rapidly with PP and
adjusts the RVR to the systolic or mean BP according to the
preparation used. The more rapid constriction than relaxation reported in preparations lacking tubules likely relates
to the absence of MD-derived NO and PGE2 that are implicated in accelerating relaxation in vivo. The times of contraction and relaxation in vivo, when measured in response
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RENAL AUTOREGULATORY MECHANISMS
to a step increase or decrease in RPP, are more symmetrical.
Moreover, the myogenic response appears to be somewhat
faster in conscious animals.
E. Vasomotion
The myogenic mechanism of most microvessels generates
oscillations in vascular tone and organ blood flow termed
“vasomotion” (1, 1169) which oscillate in vivo with frequencies of 0.05– 0.2 Hz, likely representing summation of
vasomotion in many individual small arteries (2, 854, 1087,
1408). The underlying mechanisms are still not fully understood and may even differ between vascular beds. Although
vasomotion can be induced by PP and involve similar Ca2⫹
signaling pathways as autoregulation, it has some unique
features.
Vasomotion entails the coordinated activation of VSMCs
whose oscillations in EM and [Ca2⫹]i evoke rhythmic contractions. Phasic cycles in Ca2⫹ signaling were mediated
both by periodic changes in Ca2⫹ influx and in Ca2⫹ mobilization from intracellular stores (1, 979). One proposed
sequence of events is that activation of either IP3 or RYRs/
channels on the sarcoplasmic reticulum mobilizes Ca2⫹ that
activates the plasma membrane ClCa channels to allow Cl⫺
efflux that depolarizes the membrane. The resultant activation of L-type VOCC allows Ca2⫹ entry that increases
[Ca2⫹]i further to promote MLC phosphorylation and
cross-bridge formation leading to contraction (1, 123, 529,
531). Ca2⫹ sparks (i.e., highly localized intracellular Ca2⫹
transients generated by RyRs acting on the sarcoplasmic
reticulum adjacent to the plasma membrane) also can elicit
global Ca2⫹ waves and oscillations (845). An alternative
view is that Ca2⫹ mobilization activates BKCa to cause hyperpolarization and reduce Ca2⫹ entry through L-type
VOCC and thereby cause vasodilation. Subsequently, Ca2⫹
is taken up into the sarcoplasmic reticulum via Ca2⫹-ATPase to restore the basal tone. A third scenario derives from
studies of isolated irideal arterioles whose vasomotion was
independent of EM and the endothelium and is mediated by
IP3 induced changes in [Ca2⫹]i (544).
A periodic depolarization of VSMCs generates electrical
signals that propagate along a vessel via cell-to-cell-coupling involving gap junction connections to cause synchronized oscillations in global Ca2⫹ signaling in the vasculature network (979). Oscillations are evoked by NE, KCl, or
other agents that depolarize the EM (1333, 1349). They are
dependent on gap junctions and Cxs, notably Cx37 (981).
Rhythmic Ca2⫹ signaling of VSMCs may oscillate rapidly
(⬍10 s) but can be dampened by neurotransmitters, vasoactive hormones, or local autocrine and paracrine factors
such as NO. Release of cGMP in some vascular beds may
facilitate Ca2⫹ activation of ClCa channels, perhaps via bestrophin 3, to reduce EM, thereby locking the gap junctions
between VSMCs into electrical phase (979).
430
The renal afferent arteriole studied in vitro is viewed normally as a damped oscillator that does not exhibit spontaneous vasomotion. However, in vivo oscillations of superficial cortical blood flow are readily detected, as mentioned
earlier in section IIA4B. Indeed, measurements of SNGBF
on the kidney surface in vivo reveal two oscillations driven
by the more rapid myogenic mechanism (0.15– 0.25 Hz)
and the slower MD-TGF (0.02– 0.05 Hz) (289, 625, 629,
1340, 1400, 1636). MD-TGF-mediated oscillations in PPT
have a period of 25–35 s. This slow process may oscillate
because of the relatively long delay in filtered tubular fluid
reaching the MD segment at the end of Henle’s loop to elicit
a change in arteriolar tone (626, 627, 631, 892, 893). The
faster myogenic oscillations observed in vivo with a period
of 5–10 s represent a rhythmic oscillation of vascular tone
and diameter of preglomerular vessels mediated by a coordinated and periodic fluctuation of intrinsic VSMC activity.
Afferent arteriolar oscillations of ⬃0.2 Hz with amplitudes
of ⬃1 ␮m have been detected in these renal vessels (289).
The cellular mechanisms for vasomotion of the preglomerular vasculature in vivo are thought to resemble those of the
myogenic mechanism, but have been studied more extensively in extra-renal vessels, as reviewed below.
Vasomotion was diminished in hamster skin by anesthetics
(268, 869, 1087), primarily by alternating the amplitude of
vasomotion in large arteries (653). The operating frequency
of the myogenic mechanism in the renal vasculature of SD
rats, based on transfer function gain, was 0.18 – 0.20 Hz
under barbiturate or isoflorane anesthesia, but was reduced
to ⬃0.14 Hz under halothane anesthesia (289).
Stimulation of Ca2⫹ entry in VSMCs of the HNK preparation through L-type VOCC by BAY K 8644 induced
large, 10-␮m oscillations of afferent arteriolar diameter
with a period of ⬃20 s which were dependent on RyRmediated Ca2⫹ mobilization from the sarcoplasmic reticulum (1411, 1443). An increased Ca2⫹ release was associated with an increased and more rapid constriction
which depended on Rho-kinase (1340). NE can stimulate
afferent arteriolar vasomotion and cycling of [Ca2⫹]i in
VSMCs (930, 1637). Pacemaker areas enriched in L-type
VOCCs occur at branch points along the cortical radial
arteries (477).
The requirement of the endothelium for vasomotion and
the influence of NO varied among vascular beds (1, 817).
NO acted as a stimulant in some, whereas in others, endothelium-derived factors dampened or even abolished vasomotion by desynchronizing the Ca2⫹ signals in VSMCs. For
example, vasomotion in mesenteric basilar or hamster
cheek pouch arteries was stimulated by increased NO or by
reduced KATP channel activity (1, 312) and abolished by
endothelial removal or NOS inhibition (312, 530). NO and
cGMP can modulate vasomotion at gap junctions to synchronize Ca2⫹ oscillations by inhibiting Ca2⫹ mobilization,
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CARLSTRÖM ET AL.
Ca2⫹ entry, or Ca2⫹ sensitivity (1, 530). NOS inhibition
abolished vasomotion in hamster cheek pouch arterioles by
activating K⫹ channels. cGMP facilitated vasomotion in
some (1, 477), but not other studies (312). Myogenic tone
and vasomotion were diminished in small mesenteric arteries in mice lacking caveolae with deficient NO generation
(1430).
In contrast, NO suppressed vasomotion of the rat middle
cerebral artery (336, 1645) independent of sGC but mediated by RyRs and VOCCs resulting in less synchronous
Ca2⫹ oscillations and propagating Ca2⫹ waves (1645).
TRPC1 channels in rat cerebral arteries generate oscillations in EM generated by Na⫹ entry following activation of
PLC and Ca2⫹ entry through L-type VOCCs (1620). Endothelial dysfunction in the cerebral vasculature led to lowfrequency (4 –12 cpm) spontaneous oscillations of blood
flow (635). Inhibition of oxidative stress caused oscillations
in cerebral blood flow mediated by TxA2 and TP receptors
(24, 635).
The endothelium of the small cerebral basilar arteries modulated vasomotion by direct myoendothelial coupling by
Cx37 and Cx40 that synchronized [Ca2⫹]i waves in adjacent VSMCs (542). Endothelial signaling by EDHF or TP
receptors, but not by AT1 or adrenergic receptors, also elicited vasomotion in the hamster cheek pouch microcirculation (1532). Pial arteriolar vasomotion was modulated by
somatosensory cortical neuronal activation (1536) and was
blocked by NE or ACh (1239). NOS inhibition or dibutyryl
cGMP failed to resynchronize [Ca2⫹]i waves, but K⫹ channel blockade depolarized constricted vessels and abolished
vasomotion (542).
Communication between endothelial cells was enhanced by
gap junctions consisting of Cx37, Cx40, and Cx43,
whereas VSMCs were more weakly coupled by Cx37. The
two cell types were linked by myoendothelial gap junctions
using Cx37 and Cx40. Electrotonic coupling of EM spread
a hyperpolarization wave along endothelial and VSMCs
accompanied by a propagated Ca2⫹ wave. The endothelium was essential for vasomotion in some (530, 651, 992,
1117, 1169), but not all (544, 868), studies of mesenteric
arteries and may even be promoted by removal of the endothelium or inhibition of NOS (98, 970), which can desynchronize Ca2⫹ signaling in VSMCs (1346),
PP regulated vasomotion and autoregulation. An increase
in PP of mesenteric or cerebral arteries (528) reduced the
amplitude but increased the frequency of rhythmic contractions, independent of the endothelium (529, 1135, 1525).
This was dependent on RyR-mediated Ca2⫹ mobilization
and Ca2⫹ entry through VOCCs (529, 1525). Moreover,
cyclic variations in BP in vivo modulated the arterial diameter and VSMC [Ca2⫹]i (818, 819).
Hamster cheek pouch arterioles had spontaneous vasomotion with oscillations of 20 mV in EM and 14 ␮m in diameter, which were most frequent in the smallest arterioles
(143, 268, 294). Isolated hamster cheek pouch and rat cerebral and mesenteric arterioles had both rate- and pressure-sensitive vasomotion (303, 1135, 1525). Small-amplitude, positive-pressure steps elicited monophasic constriction, whereas higher pressure steps elicited biphasic
constrictions that were only partially dependent on a myogenic mechanism.
Measurements of oscillations of blood flow have been used
to study myogenic mechanisms in humans. Spectral analysis
of microcirculatory peripheral blood flow in the skin of the
hand and sternum by laser Doppler flowmetry showed two
principal spectral rhythms of 0.04 – 0.15 Hz and ⬃0.17 Hz
(907), which reflected myogenic activity (1262). Whereas
the skin of the leg had more myogenic (0.05– 0.14 Hz) activity than the forearm at 33°C (622), this was reversed by
warming to 42°C. Insulin increased the amplitude of the
myogenic vasomotion in human skin, (1262), as in rat skeletal muscle (1085). A large-amplitude ⬃0.1 Hz oscillation
in cerebral cortical perfusion was observed in conscious
humans in association with wave-like propagation and oscillations in the diameter of pial arterioles (1211). The lowfrequency oscillations (⬃0.1 Hz) of cerebral blood flow
were reduced in the aged (1533).
In summary, a key component of vasomotion is spontaneous oscillation of EM that is generally mediated by either
ClCa or BKCa channels to modulate Ca2⫹ entry through
L-type VOCCs. This is followed by a prominent role for
RyRs in triggering Ca2⫹ mobilization. The contribution of
voltage-dependent channels and the endothelium varies
among vessels (543). Cell coupling by gap junctions enhances synchronization of oscillations in Ca2⫹ release
among adjacent cells, at least in isolated vessels in vitro. The
speed of the myogenic mechanism varies by vascular bed. It
is generally most rapid in the renal microcirculation (0.2
Hz), followed by the cerebral and mesenteric vascular beds
(⬃0.15 Hz), with slower vasomotion in the cutaneous network (0.05– 0.15 Hz). Smaller arteries and arterioles have
higher frequency oscillation than large vessels. Recent studies of oscillation in blood flow have given promise of a new
technique to study myogenic mechanisms in the human circulation.
III. MECHANOSENSITIVE MECHANISM
INITIATING THE MYOGENIC RESPONSE
Mechanotransduction implies an integrated interaction of
the extracellular environment with the three-dimensional
structure of the vessel wall that links changes in membrane
stretch to intracellular signaling mechanisms (678, 899).
Pressure-induced deformation of extracellular matrix proteins and their cell surface receptors such as integrins are
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RENAL AUTOREGULATORY MECHANISMS
thought to initiate contraction and cytoskeletal remodeling
through modulation of ion channels, membrane depolarization, increased [Ca2⫹]i, and actomyosin crossbridge cycling (304, 617). Thus integrin interaction with the extracellular matrix transduced extracellular mechanical forces
such as shear and tension into intracellular biochemical
signals to affect VSMC contractility (64, 213, 304). Myogenic constriction of VSMCs resulted from activation of
VOCCs secondary to reduced EM (301, 562, 810). Activation of mechanosensitive ion channels initiated pressureinduced depolarization and subsequent Ca2⫹ signaling and
myogenic constriction.
was initiated by localized RyR-dependent Ca2⫹ sparks that
amplified global [Ca2⫹]i waves (214). Blockade of RyRs
inhibited integrin-mediated myogenic constriction of afferent arterioles (FIGURE 8) (64). RyR-dependent Ca2⫹ signaling was independent of Ca2⫹ entry via L-type VOCCs in the
renal (214), but not in nonrenal vessels (525). Ca2⫹-induced Ca2⫹ release in the afferent arteriole may be more
critical in the initiation of the myogenic response than in the
sustained phase when Ca2⫹ entry through VOCCs is essential. Mechanical force that perturbed the interactions between fibronectin and ␣5␤1 integrins prolonged the oscillatory Ca2⫹ signals and the tractional force developed by
renal VSMCs (65).
A. Integrins
How integrins detect mechanical distortion is poorly understood. The mechanosensitive myogenic response of cerebral
arteries involves cytoskeleton remodeling and actin polymerization (262). Changes in the intraluminal pressure of
arterioles may cause conformational changes of the extracellular matrix and fibronectin that expose binding sites for
integrins, which trigger an intracellular signaling cascade.
Alternatively, integrins may sense the distending force directly and signal across the extracellular-integrin-cytoskeleton axis. Disruption of the cytoskeleton can impair the
myogenic response. Deletion of the serum response factor in
endothelial cells or VSMCs of tail arteries markedly attenuated myogenic constriction and reduced actin polymerization, myosin light chain, and myosin light chain kinase
(1234) while maintaining vasoconstriction produced by PE
or U-46619. At present, the specific actions of particular
integrins in the renal microcirculation are unclear, but they
likely constitute an important component of arteriolar
mechanosensation.
Integrins are a diverse family of transmembrane heterodimeric proteins composed of one ␣- and one ␤-subunit that
link the extracellular matrix to the cytoskeleton of VSMCs.
Deformation of integrins during changes in cell shape or
stress conducts pressure-induced signals across the plasma
membrane (304, 525, 614) to activate protein tyrosinephosphorylation cascades and mitogen-activated protein
kinases (MAPKs) including extracellular receptor kinases
(ERKs) (614). Although inhibition of ERK in rat cerebral
arteries inhibited myogenic constriction and KCl-induced
tone (857, 1600), the dynamics of PP-induced tyrosine
phosphorylation in rat cremaster arterioles was considerably slower than the myogenic response, which argues
against a causal relationship (1045, 1046). Both L-type
VOCCs and BK channels in isolated VSMCs and cremaster
arterioles were regulated by ␣5␤1 integrins that interacted
with fibronectin in the extracellular matrix to cause c-Srcmediated phosphorylation (305, 525). Thus both VOCCs
that excite the myogenic response and BK channels that
generally inhibit the response are under constitutive control
by an interaction between ␣5␤1 integrins and fibronectins.
The balance of their activities could determine the degree of
pressure-induced myogenic tone and perhaps vascular remodeling (525).
Rat afferent arteriolar VSMCs expressed the ␣3-, ␣5-, ␣Vand the ␤1-, ␤3-integrin subunits (1638). A synthetic peptide with an arginine-glycine-aspartic acid (RGD) motif
that interacts with integrin binding sites mobilized Ca2⫹
and contracted VSMCs (1638). In contrast, a different peptide with a RGD sequence reduced [Ca2⫹]i and dilated rat
cremaster arterioles (291). Thus there is an extensive diversity and regional specificity among this group of proteins
with other residues possibly playing a role. As discussed in
the introduction, the embryological origins of VSMCs differ according to their vascular bed and thus may contribute
to this diversity.
Shear stress in preglomerular VSMCs was transduced by
cell surface ␣5␤1 integrins into cytoskeleton-dependent
Ca2⫹ release from sarcoplasmic reticular stores (64). This
432
B. ENaCs
The ENaC in the CT and CDs is a trimeric protein complex
composed of ␣-, ␤-, and ␥-subunits, which facilitates the
Na⫹ reabsorption that initiates CT-GF. A vascular ␤-ENaC
has been proposed to function as a pressure- or stretchsensitive mechanosensor by forming an ion channel with
degenerin (DEG) that is a closely related neuronal acidsensing ion channel (ASIC) that is tethered to the extracellular matrix and cytoskeletal proteins (343, 344, 346,
1431). The non-voltage-gated ␤-ENaC-DEG complex may
permit Na⫹ entry in response to increased intraluminal
pressure and thereby cause depolarization of VSMC to initiate the myogenic response (FIGURE 8) (728). Stretch activation of ␤-ENaC in mouse freshly isolated renal VSMCs
increased Na⫹ entry (258), whereas in the CD, shear stress
gated and opened ENaCs (1356).
Rat cerebral arterial VSMCs expressed ␤- and ␥-ENaC subunits (344). Most, but not all, of the myogenic constrictor
tone was inhibited by blockade of ENaC with amiloride (1
␮M) or benzamil (30 nM) (344). Likewise, amiloride, ben-
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CARLSTRÖM ET AL.
PERFUSION PRESSURE
VOCC
ENaC
+Deg
GPCR
PLC
Membrane
events
TRPC
Integrins
DAG
ADP
ribosyl
cyclase
Em
p47phox
NAPDH
oxidase
cADPR
[Ca2+]i
GPCR
RyR
ROS
PLC
Cytosolic
signaling
Ca2+ induced
IP3 R
Ca2+ release
IP3
DAG
Rho / rho
kinase
PKC
Actin / myosin
crosslinking
Myosin light
chain kinase
Myosin light
chain phosphotase
Contractile
response
MYOGENIC CONTRACTION
FIGURE 8. An overview of the major pathways proposed to mediate or modulate the renal afferent arteriolar
myogenic contractile response to an increase in perfusion pressure (PP). The mechanisms are grouped as
membrane events, cytosolic signaling events, and contractile responses. VOCC, voltage-operated calcium
channel; ENaC, epithelial Na⫹ channel; DEG, degenerin; GPCR, G protein-coupled receptor; TRPC, transient
receptor potential channel; PLC phospholipase C; DAG, diacylglycerol; Em, membrane potential; cADPR, cyclic
ADP-ribose; NADPH, nicotinamide adenine dinucleotide phosphate; [Ca2⫹]i, cytosolic concentration of ionized
calcium; RyR, ryanodine receptor; ROS, reactive oxygen species; IP3R, inositol trisphosphate receptor; PKC,
protein kinase C. For discussion, see text.
zamil (1 ␮M) or siRNA knockdown of ␤- or ␥-ENaC subunits attenuated some of the myogenic constriction in rat
posterior cerebral arteries (793). Myogenic constriction of
middle cerebral arteries of ASIC2 knockout mice was very
weak, whereas constrictor responses to high KCl and PE
were normal, suggesting specificity to mechanical stimulation (454). DEG-like currents in cerebral arterial VSMCs
were inhibited by ROS (257). ␤-ENaC in rat posterior cerebral arteries colocalized with TRPM4 but not TRPC6
(793, 794), although all three channels participated in myogenic constriction.
ENaC ␣- and ␥ -subunit expression in mesenteric arteries
was reduced by high-salt diet, whereas ␤-ENaC movement
to the plasma membrane of VSMCs was increased (730).
Benzamil (1 ␮M) inhibited the myogenic response only in
arteries from rats fed a high-salt diet (730).
There is controversy about the presence of mRNA and protein for specific ENaC subunits in VSMCs of the cortical
radial artery and afferent arteriole. Early studies of single
VSMCs in the renal microcirculation, either freshly isolated
or cultured from relatively large cortical radial arteries of
rats or mice, reported expression of ␤- and ␥-, but not ␣-,
ENaC protein subunits (729). However, subsequent immunofluorescent studies in VSMC freshly isolated from cortical radial arteries and afferent arterioles revealed expression of ␣- as well as ␤- and ␥-subunits of ENaC (522). The
finding of the ␣-subunit poses a potential problem with
ENaC serving as a mechanosensitive channel since it renders the ion channel constitutively active and thus not selectively responsive to a change in transmural pressure
(522). On the other hand, another study failed to detect
mRNAs for any ENaC subunits in VSMCs disassociated
from these arterioles (1574), but all three subunits were
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RENAL AUTOREGULATORY MECHANISMS
evident in intact cortical radial arteries. This implicates expression of ENaC on endothelial or adventitial cells rather
than on VSMCs, which would not be compatible with a
mechanosensing function.
Varying results have been reported for pharmacological
blockade of ENaC channels depending on the concentrations of antagonists. Apparent blockade of ENaC activity
with 5 ␮M amiloride or benzamil or genetic knockdown of
either ␤- or ␥-ENaC subunits attenuated myogenic constriction of cortical radial arteries (344, 728, 729). Moreover,
ANG II infusion reduced the immunoreactive expression of
␤- and ␥-ENaC in rat interlobar arteries and reduced myogenic contraction (731). However, the majority of the myogenic response and the regulation of RVR in vivo occur in
smaller, more distal cortical radial arteries and afferent arterioles rather than in the relatively large interlobar arteries
(201, 611, 1071). Nevertheless, recent studies have reported an impaired myogenic constriction of afferent arterioles isolated from mice with genetically reduced ␤-ENaC
expression (462).
A mouse model of genetically reduced (⬃50%) ␤-ENaC
expression had a 50% reduction in the myogenic component of RBF autoregulation in the 0- to 5-s time window, yet
a well-maintained overall steady-state autoregulation
(505). This likely implies that the MD-TGF contribution
was upregulated since inhibition of MD-TGF by acute volume expansion revealed a 75% reduction in the whole kidney myogenic response in mice with genetic reductions in
␤-ENaC expression and almost complete loss of autoregulation over 30 s after a step change in PP (462).
Recent studies by Drummond and associates using VSMCs
freshly isolated from the mouse afferent arteriole have
shown less frequent and smaller stretch-activated Na⫹ currents in the VSMCs from mice with reduced ␤-ENaC expression, but preserved VOCC and BK channel activity
(258, 344). Thus ␤-ENaC appears to be required for normal
mechanically gated currents in renal VSMCs. Their disruption reduces myogenic constriction of afferent arterioles.
Cortical radial arteries and afferent arterioles isolated from
␤-ENaC knockdown mice have a weakened myogenic tone,
but constricted normally to PE and KCl (462), which implies that ENaC is upstream from myogenic contractions.
Mice with partial gene knockdown of ␤-ENaC became hypertensive and developed renal inflammation and damage
that may be related to reduced renal autoregulatory capacity (345).
The myogenic response of the rat perfused JMN preparation after papillectomy to eliminate MD-TGF was blunted
by blockade of ENaC with 10 ␮M amiloride or benzamil
added to the bath or 5 ␮M amiloride added to the luminal
perfusate (522). Similarly, relatively high concentrations of
inhibitors of ENaC (amiloride and benzamil, 10 ␮M)
434
blocked more than two-thirds of the autoregulatory response of the afferent arteriole, whereas vasoconstriction
produced by ATP or 20-HETE was unaffected (1051). The
authors concluded that ENaC is an essential component of
myogenic responses.
Different conclusions were reported in a recent study with
the HNK preparation where the myogenic response or the
EM was unaltered by relatively low concentrations (ⱕ1–3
␮M) of amiloride or benzamil which inhibited ⬎80%
ENaC activity in renal tubules (926, 1574). However,
higher concentrations (ⱖ5 ␮M), similar to those used in the
earlier studies, were confirmed to inhibit myogenic constriction, but this was ascribed to nonspecific inhibition of Na⫹
transporters and ion channels other than ENaC (926).
Moreover, myogenic constriction in the rat HNK preparation was independent of extracellular [Na⫹] (1574). Benzamil (ⱖ1 ␮M), which also inhibits the NCX exchanger,
depolarized and potentiated, rather than inhibited, the
myogenic constriction of the afferent arteriole in this study
(1574). However, another study of afferent arterioles of the
HNK reported that lowering extracellular [Na⫹] led to a
slowly developing attenuation of myogenic constriction,
with abolition of the myogenic response when [Na⫹] was
below 50 mM (1446).
Aldosterone regulates ENaC expression and activity in the
distal nephron, but less is known about its role in the regulation of ENaC in VSMCs and endothelium. Elevated aldosterone levels are causally linked to vascular fibrosis, inflammation, and remodeling (152, 816). Stretch of rat cultured aortic VSMCs increased nicotinamide adenine
dinucleotide phosphate (NADPH) oxidase activity that was
dependent on aldosterone and mineralocorticoids (1114).
Aged mice lacking mineralocorticoid receptors in their
VSMCs were hypotensive and had a 40% reduced myogenic tone in their mesenteric arteries, weaker TP receptorinduced contraction, and an 80% reduction in the expression and activity of L-type VOCC, whereas BKCa function
was normal (994). Aldosterone rapidly (⬍5 min) contracted rabbit isolated afferent and efferent arterioles via
nongenomic mechanisms mediated by L- and/or T-type
VOCC (53, 54).
ENaC is also located in the vascular endothelium of mesenteric arteries where it inhibited NO production (851),
which might be another pathway whereby ENaC modulates the myogenic mechanism.
In summary, genetic studies with knockdown of ␤-ENaC in
the preglomerular vasculature have reported an attenuated
myogenic response, implicating ␤-ENaC as a critical
mechanosensor. However, the pharmacological evidence
for a role of ENaC is more controversial because of lack of
specificity of the antagonists at the concentrations tested.
Integrins could function as force transducers linked to
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ENaC as part of a mechanosensory complex that couples
the extracellular matrix to the cytoskeleton. In turn, ENaC
may be linked directly or indirectly to TRP channels. Further investigation is required to clarify whether and how
ENaC subunits function as mechanosensors in the renal
microcirculation.
C. Transient Receptor Potential Channels
and Stretch-Activated G Protein-Coupled
Receptors
Transient receptor potential (TRP) channels are a family of
voltage-insensitive, homo- or heterotetrameric proteins that
function either as nonselective cation channels allowing entry of Ca2⫹ and Na⫹ to depolarize the EM or as highly
selective Ca2⫹ channels to directly increase [Ca2⫹]i (FIGURE
8) (330, 366, 368, 681, 1352). Either mechanism could
cause vasoconstriction. TRPC1, TRPC3, and TRPC6 are
abundant in VSMCs. TRP channels resided in signaling
complexes in caveolar lipid raft domains in the plasma
membrane (23). Mechano-gating of TRPC1 and TRPC6
can be transduced through scaffolding proteins and actin
filaments of the cytoskeleton.
The mRNAs and proteins for multiple canonical (C) TRPs
have been identified in rat renal resistance vessels and glomeruli. The mRNAs for TRPC1, 3, 4, 5, and 6 were expressed
in renal cortical radial arteries and afferent arterioles (387),
and the proteins for TRPC1, 3, 5, and 6 have been detected
in glomeruli and preglomerular vessels (387, 1278). TRPC1
was expressed both in the afferent and efferent arterioles
(1448). Immunoreactive TRPC1, 3, and 6 were expressed
on rat afferent arteriolar VSMCs and TRPC3 on cortical
radial arteries (1278).
Mechanical stretch of the plasma membrane directly activated TRPC6, presumably via a conformational change to
open the channel, independent of GPCR ligand binding or
PLC activation, in HEK293 and CHO cells overexpressing
the ion channel (1403). DAG generation after GPCR activation can engage TRPC3 and TRPC6 channels in VSMC
throughout the vasculature (623, 679). In cerebral vessels,
TRPC6 and TRP melastatin (M) 4 and vanilloid (V) channels transduce myogenic responses (141, 366, 371, 681,
1352, 1403, 1594). Cerebral arterial VSMCs also express
TRPC3 that is activated by GPCR agonists such as UTP but
not by pressure, suggesting coupling of TRPC3 and TRPC6
to distinct excitatory stimuli (1212). TRPC1 was present in
VSMC of cerebral arteries, but it is not clear if it has a
mechanosensitive role in the vasculature (331).
These findings led to the concept that membrane stretch
activates a TRPC6-dependent constriction of cerebral arteries. A proposed pathway is that membrane stretch activates
PLC to produce DAG, which directly activates TRPC6 to
mediate depolarizing cation current to trigger a myogenic
response (679). Thus pressure-induced depolarization of
cerebral artery myocytes was blocked by PLC inhibition
(1383), and mechanosensitive channels in VSMCs resembling TRPC channels were inhibited by PLC blockade and
activated by a DAG analog (1154). However, mechanosensitive channel activity and myogenic responses of cerebral
arteries were not affected by deletion of TRPC1 (331) or
TRPC6 (332, 490). 20-HETE potentiated the activity of
TRPC6 channels of the mesenteric artery, thereby enhancing myogenic constriction (680).
TRPC6 on the glomerular podocyte slit diaphragm functioned as a mechanosensor coupled to Ca2⫹-activated potassium (KCa) channels (348). Stretch activation of cation
entry in the podocyte was independent of PLC or PLA2
activity (25). Gain-of-function mutations of TRPC6 caused
podocyte dysfunction and focal and segmental glomerulosclerosis (FSGS) (372, 837), whereas deletion of TRPC5
protected mice from albuminuria (1290).
IP3 constricted cerebral arteries via TRPC3 channel activation leading to Na⫹ influx and membrane depolarization,
independent of sarcoplasmic reticular Ca2⫹ release (1629).
A similar mechanism operated in rat mesenteric arteries
where IP3 coupling of TRPC3 channels to caveolae resulted
in Na⫹ entry (10).
TRPM4 in cerebral artery myocytes was a highly selective
monovalent cation channel activated by stretch or Ca2⫹
entry through TRPC6 channels and/or Ca2⫹ mobilization
mediated by RyRs (370, 1032). Other studies in cerebral
arteries reported that transmural pressure activated a signaling cascade involving activation of Src tyrosine kinase
and PLC with subsequent IP3 generation that mobilized
Ca2⫹ from the sarcoplasmic reticulum (480 – 482). The resultant increase in [Ca2⫹]i in turn activated plasma membrane TRPM4 that increased Na⫹ entry and depolarized
the plasma membrane to allow Ca2⫹ entry and contraction.
The Ca2⫹ activation of TPRM4 may be enhanced by Ca2⫹
entry through TRPC6 channels. In contrast, TRPV4 in mesenteric arteries acted as a nonselective cation channel activated by stretch or EETs to cause activation of K⫹ channels
that hyperpolarized the plasma membrane and relaxed the
vessel (367).
A provocative observation was that hyposmotic cell swelling and stretch-activated G protein-coupled receptors (GPCRs) that caused a conformational change independent of
ligand binding which conferred a mechanosensitive action
on TRPC6 in heterologous systems overexpressing GPRC
and TRPC6 (1403). GPCR activation in VSMCs linked to
Gq/11-dependent DAG generation can engage TRPC6 channels in VSMCs independent of PKC (FIGURE 8) (1143).
Subsequent studies demonstrated that stretch activation of
GPCRs stimulated cation flux through TRPC3 and TRPC6
via PLC-dependent DAG formation (1000). Diverse GP-
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RENAL AUTOREGULATORY MECHANISMS
CRs may activate this pathway including ANG II type 1
(AT1), endothelin type A (ETA), vasopressin type 1A (V1A),
and muscarinic type 5 (M5) receptors (1000, 1673). In the
absence of ANG II, certain antagonists of AT1 receptors,
such as losartan or candesartan, prevented stretch-induced
myogenic tone of cerebral and renal cortical radial arterial
VSMCs via reductions in ERK and ROS (999, 1000). The
myogenic tone of cerebral arteries was enhanced by activation of GPCRs linked to PLC-sensitive G proteins (1137),
whereas TRPC3 in cerebral arteries was activated by IP3,
independent of Ca2⫹ release from the sarcoplasmic reticulum (1629). Collectively, these data suggest that membrane
stretch causes an agonist-independent conformational
change in the GPCR, which activates PLC and downstream
G␣q/ll signaling to cause DAG activation of TRPC6, resulting in Na⫹ and/or Ca2⫹ entry, membrane depolarization,
and a myogenic response (1000, 1421).
A recent study extends these findings to individual mesenteric arteries and isolated kidneys. This demonstrated a requirement for AT1A receptors for myogenic responses in the
absence of its native ligand (1294). However, the downstream signaling relies on an ion channel distinct from
TRPC6 or a Kv channel distinct from KCNQ3, 4, or 5 to
activate VSMCs and elevate vascular resistance.
Renal function studies raise some questions about the role
of GPCR in the myogenic response. Although ANG II may
potentiate the renal myogenic response, as discussed in section VIA, activation of other GPCR by natural agonists
such as adrenoceptors by catecholamines (760, 1193,
1570), ETA receptors by endothelin (1357), or V1A receptors by AVP (1563) do not normally impact the renal myogenic response. Frequency analysis in the kidney generally
has found that inhibition of ANG II formation (597) or AT1
receptor antagonism (329) has little effect on the myogenic
mechanism, although a recent study reported that prolonged ANG II administration potentiated the renal myogenic response (1193). In other studies, blockade of AT1
receptors with losartan or candesartan did not inhibit myogenic tone in rat mesenteric arteries (519, 985) and only
blunted myogenic constriction of cerebral arteries weakly
(1000).
G␣q/ll-coupled receptor activation in cerebral arteries by
uridine triphosphate or thromboxane prostanoid (TP) receptor activation by U-46619 did not enhance mechanosensitivity of TRPC-like currents or amplify myogenic responsiveness (36). Increasing the PP of rat isolated mesenteric
arteries activated ERK1/2 that was inhibited by an antagonist of AT1 but not AT2 receptors (383, 984). The myogenic
response was also blocked during ACE inhibition, suggesting dependence on ANG II formation.
At present, limited data have implicated an agonist-independent, stretch-activated GPCR pathway in TRP channel
436
activation of the myogenic contractile response in renal microvessels. Thus myogenic tone of renal arteries was diminished by the AT1 receptor antagonist losartan independent
of ANG II (1000). Cortical radial arteries from regulator G
protein signaling 2 knockout mice had enhanced myogenic
tone in addition to the expected exaggerated vasoconstriction to ANG II, ET-1, and PE (604).
Activation of TRPC channels in the afferent arteriole enhanced Ca2⫹ signaling by ANG II (402) and NE where they
functioned as store-operated cation channels (SOC) independent of L-type VOCCs (387, 1278). The myogenic response of cortical radial arteries and afferent arterioles of
the HNK depended on ill-defined mechanosensitive cation
channels (1446, 1447). GPCRs can activate redox signaling
in afferent arteriolar VSMCs (399, 400, 1606) where TRP
channels themselves are redox sensitive because of oxidative modifications of specific cysteine residues (507, 1005,
1433). VOCCs also were redox regulated (126). NO activated TRPC channels via cysteine S-nitrosylation (1639).
The polycystins represent a special class of TRP cation
channels. VSMC TRP polycystin-1 and -2 (TRPP1 and -2)
cation channel proteins modulated the myogenic response
in mesenteric arteries (1057). Deletion of TRPP1 in VSMCs
reduced stretch-activated channel activity and myogenic
tone (1353), but depletion of TRPP2 rescued both stretchactivated channel opening and the myogenic response, indicating extensive interaction. TRPP2 interacted with the
cytoskeleton and an actin crosslinking protein that was central for stretch-activated channel regulation.
In summary, cation entry through TRP channels subserves
two functions in VSMC: to relate changes in transmural
pressure or stretch to depolarization of the plasma membrane and to respond to GPCR stimulation and PLC activation to modulate SOC function. TRP channels are attractive candidates as mechanosensors, but their linkage to GPCRs remains an intriguing, but uncertain, possibility. The
specific roles of particular TRP channels acting as mechanosensors initiating membrane depolarization and increases in [Ca2⫹]i to trigger the myogenic response of afferent arterioles requires further clarification. Integrins, signaling through the cytoskeleton and possible TRP channels are
attractive candidates, but are incompletely studied in the
renal microcirculation. The role of stretch-activated ENaC
channels is controversial and still evolving.
IV. CONDUCTANCE CHANGES MEDIATING
MYOGENIC CONTRACTION
A. Chloride Channels
The intracellular [Cl⫺] in VSMCs is high due to accumulation by a Cl⫺/HCO3⫺ exchanger and the NKCC1 cotransporter. Because the [Cl⫺] in VSMCs is above its electro-
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CARLSTRÖM ET AL.
chemical equilibrium, activation of plasma membrane Cl⫺
channels permits Cl⫺ efflux, leading to depolarization of the
plasma membrane, with subsequent opening of VOCCs to
promote Ca2⫹ entry (489, 1324, 1442). However, the resting Cl⫺ permeability of VSMCs (621), arcuate arteries
(1200), and renal mesangial cells (1118) is sufficiently low
that the EM is unaffected by removal of extracellular Cl⫺.
Likewise, the basal tone of rabbit perfused afferent arterioles is unchanged in Cl⫺-free media (726). These results
indicate that there is little basal Cl⫺ conductance in afferent
arterioles.
On the other hand, VSMCs isolated from arcuate or cortical
radial arteries display a Ca2⫹-activated Cl⫺ conductance
(ClCa) that depolarizes the plasma membrane after GPCR
activation and leads to Ca2⫹ mobilization (489, 664). ClCa
channels in afferent arterioles contribute to membrane depolarization (559), Ca2⫹ entry (1324), GPCR activation
(726, 1442), and increased [Ca2⫹]i produced by ANG II or
ET-1 (451, 727, 1324, 1435). GPCR activates Cl⫺ channels
in mesangial cells to depolarize the plasma membrane and
enhance [Ca2⫹]i signaling (834, 987).
Activated Cl⫺ channels also can enhance myogenic tone by
providing a Cl⫺ influx pathway as a charge compensation
for influx of Ca2⫹ during activation of VOCCs (559, 726).
Indeed, the addition of extracellular Cl⫺ enhanced high
K⫹-induced depolarization and VOCC-dependent contractions of rabbit afferent arterioles with an EC50 of 82 mM
(559), that is close to [Cl⫺] in extracellular fluid, while
removal of extracellular Cl⫺ attenuated Ca2⫹ influx via
VOCCs in both mesangial cells (834) and rat aortic VSMCs
(1650).
Although Cl⫺ channels are important in vasoconstriction of
afferent arterioles produced by ANG II and NE (559, 726,
1407), neither blockade of Cl⫺ channels nor reducing extracellular [Cl⫺] inhibits myogenic responses of the HNK
preparation (1435, 1442). Thus ClCa regulated VOCCs
during stimulation with GPCR agonists, but these channels
do not appear to be required for the myogenic response of
afferent arterioles (726, 1442).
The electroneutral NKCC1 is present in VSMCs throughout the vascular system, in contrast to the NKCC2 isoform
that is expressed exclusively in the kidney in the TAL of
Henle’s loop and MD cells. NKCC1 may regulate myogenic
tone of arteries and arterioles. Ion entry via NKCC1 increased intracellular [Cl⫺] that caused membrane depolarization and thereby Ca2⫹ entry through VOCCs and vasoconstriction (1126). Indeed, afferent arteriolar myocytes
expressed NKCC1 but not NKCC2 (1568), and inhibition
of this vascular NKCC1 in the mouse isolated and perfused
afferent arteriole by furosemide or bumetanide caused vasodilation (1124) and inhibited most of the myogenic response of the afferent arteriole in the rat HNK preparation
lacking tubules (1568). Inhibition of NKCC1 by bumetanide decreased myogenic tone in mesenteric arteries as well
as contraction by high KCl, PE, and UTP (820).
However, as discussed in section IVC, such pronounced
inhibition of myogenic tone has not been observed during
administration of furosemide or bumetanide in vivo. RBF in
vivo is usually unchanged or slightly reduced during furosemide-induced natriuresis (749 –751, 753, 760, 1124,
1183, 1489), although increased RBF has been observed in
some cases (170, 351, 760). Tubular hydrostatic pressure
and interstitial hydrostatic pressure was increased during
furosemide-induced natriuresis (170, 1489), which may
contribute to a fall in GFR.
Molecular candidates for Cl⫺ channels are transmembrane
protein 16A (TMEM16A) or anoctamin 1 (ANO1), bestrophins, as well as the classic ClC-3 (1367). Both “classic”
and cGMP-dependent ClCa channels are expressed in
VSMCs. Bestrophin-3 is reported as a cGMP-dependent
Ca2⫹-activated Cl⫺ conductance and ClC-3, a voltagegated channel (980, 982). Membrane stretch in cerebral
arteries activated TMEM16A channels in VSMCs and
caused membrane depolarization and the myogenic response via cation entry through mechanosensitive nonselective cation channels, with Ca2⫹ activation of TMEM16A
facilitating Cl⫺ efflux (165). Disruption of TMEM16A
(ANO1) and thereby preventions of Ca2⫹-activated Cl⫺
currents relaxed VSMC of aorta and carotid arteries (599).
Blockade of Cl⫺ channels in pressurized rat cerebral arteries
caused hyperpolarization (⫺10 to ⫺15 mV) that inhibited
myogenic tone (1080).
Bestrophin-3 was important for Ca2⫹ oscillations and synchronization of VSMC during vasomotion in the rat mesenteric small arteries in vivo (153). siRNA knockdown of
bestrophins in rat mesenteric arteries did not affect arterial
contraction but inhibited the rhythmic contractions, vasomotion (295). Downregulation of TMEM16A also reduced
expression of bestrophins and suppressed vasomotion and
contractions produced by GPCR agonists (NE, AVP) and
KCl, suggesting this ClCa channel participates in depolarization of VSMC.
Thus Cl⫺ channels are involved in the regulation of the EM
of VSMC and vasoconstriction of mesenteric arteries and
myogenic tone of cerebral arteries. Cl⫺ channels in the renal
vasculature participate in vasoconstriction by GPCR agonists, but apparently not the myogenic response.
B. Potassium Channels
The resting EM of VSMCs of pressurized afferent arterioles
is approximately ⫺40 mV. This is ascribed largely to a K⫹
diffusion potential. The EM was near the threshold for activation of L-type VOCCs (847, 928). Opening K⫹ channels
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RENAL AUTOREGULATORY MECHANISMS
and potentiating K⫹ efflux from VSMCs elicits vasodilation
primarily by hyperpolarization that inactivates L-type
VOCCs and reduces Ca2⫹ entry. The large-conductance,
Ca2⫹-activated K⫹ channel (BKCa) in the cerebral circulation was a major determinant of the VSMC EM (1081).
The BKCa channel has been implicated in several steps of the
myogenic response, including channel closure causing
membrane depolarization, and channel opening causing hyperpolarization to oppose excessive pressure-induced vasoconstriction. A special case in cerebral arteries is spontaneous or pressure-induced Ca2⫹ sparks representing Ca2⫹ release from RyR channels in the sarcoplasmic reticulum,
which can activate BKCa to hyperpolarize the plasma membrane, limit Ca2⫹ entry via VOCCs, and diminish myogenic
tone. Accordingly, inhibition of BKCa in many nonrenal
vascular beds has a variable effect, but often depolarizes the
EM and enhances stretch-induced depolarization, Ca2⫹ entry, and contraction (720, 1595).
Caveolae in VSMC of cerebral arteries can modulate the
myogenic response. VSMC of mice lacking caveolin-1 responded to an increased pressure with a diminished depolarization, an increase in [Ca2⫹]i, and myogenic response
(11) via activation of BKCa channels and hyperpolarization.
NOS inhibition did not restore myogenic tone in arteries
deficient in caveolin-1, arguing against excess NO production as the cause for inhibition of the myogenic response.
Genetic ablation of caveolin-1 in murine cerebral artery
VSMCs increased Ca2⫹ sparks and the frequency of transient BKCa currents without altering Ca2⫹ entry via VOCC
(233).
Stretch of VSMCs in coronary arteries/arterioles and mesenteric arteries stimulated an outward K⫹ current through
BKCa, whereas blockade of BKCa channels enhanced
stretch-induced depolarization (338, 1628). Inhibition of
BKCa channels increased myogenic contraction of pressurized mouse mesenteric arteries, presumably by favoring
membrane depolarization and Ca2⫹ entry through VOCCs
(836).
VSMCs exhibit heterogeneity in BKCa activity or their sensitivity that may contribute to tissue-specific differences in
the regulation of myogenic vasoconstriction (525, 618,
1632). For example, the BKCa is more sensitive to increased
[Ca2⫹]i resulting from Ca2⫹ sparks generated by Ca2⫹ release from sarcoplasmic reticulum in cerebral than skeletal
muscle cremaster arteries. The resultant vasodilation attenuated myogenic vasoconstriction in cerebral arteries
(1632). The variation in sensitivity might be explained by
the number of ␤1 subunits of the BKCa channel (1632).
The extent to which BKCa are open during basal conditions
and modulate basal EM in the renal vasculature is not clear.
BKCa channels are present on VSMCs of preglomerular ar-
438
teries and arterioles (390, 467, 949, 1200), but usually are
closed under basal conditions. Thus their blockade did not
modify resting RBF or renal vasoconstriction elicited by
ANG II or NE (949). Moreover, BKCa channels in pressurized afferent arterioles of JMN also were quiescent and did
not buffer vasoconstriction by ANG II (390, 1200). ACh
caused dose-dependent renal vasodilatation in isolated perfused rat kidneys, which was blunted by NOS inhibition but
not by inhibition of sGC. The vasodilation was mediated by
KCa3.1 channels sensitive to charbdotoxin which is characteristic of BKCa channels (1370).
On the other hand, an increase in PP of renal arterioles was
reported to increase 20-HETE generation from arachidonate, which closed BKCa channels and thereby caused membrane depolarization and vasoconstriction (672, 943,
1667). Blockade of 20-HETE production inhibited myogenic responses of arcuate arteries and impaired RBF autoregulation (464, 777, 1668, 1669).
Voltage-gated and inward-rectifier K⫹ channels (KV and
KIR) in afferent arterioles can regulate basal vascular tone
(936, 1484). KIR 2.1 in the afferent arteriole contributed to
K⫹ currents and EM of VSMCs (238). Enhanced rectification of KIR in the distal cortical radial artery and afferent
arteriole hyperpolarized the plasma membrane and attenuated myogenic tone (239, 240). Stimulation of PKC by
ANG II or ET-1 potentiated the myogenic response of afferent arterioles of the HNK preparation by inhibition of
delayed rectifier K⫹ channels which depolarizes the plasma
membrane (802).
Activation of ATP-dependent K⫹ channels (KATP) in JMN
had no effect on basal afferent arteriolar tone (665), but
blunted PE-induced constriction of rabbit afferent arterioles (924). Activation of these channels by calcitonin generelated peptide dilated the afferent arteriole in the HNK
preparation (1232) by causing hyperpolarization of the
plasma membrane that inhibited Ca2⫹ entry through
VOCCs (1231). Moreover, activation of KATP by pharmacological agents or hypoxia hyperpolarized the plasma
membrane and inhibited myogenic responses of afferent
arterioles (936, 1232). However, KATP channels in the dog
did not affect the MD-TGF response (782) or the autoregulation of coronary blood flow (1060).
A recent study of the renal vasculature in rats in vivo demonstrated that pharmacological blockade of individual K⫹
channels (e.g., BKCa, Kir, KATP, Kv) had little effect on large
whole kidney RVR responses to GPCR agonists such as
ANG II or NE and their activation of VOCCs (1396). However, concurrent closure of multiple types of K⫹ channels
effectively attenuated agonist-induced renal vasoconstriction, demonstrating considerable redundancy among the
K⫹ channels in the renal microcirculation. Although voltage-dependent K⫹ channels were tonically active in coro-
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CARLSTRÖM ET AL.
nary arteries, they were not required in vivo for autoregulation (99). KCNQ (Kv7) K⫹ channels in cerebral arteries
were inhibited by membrane stretch and thereby could
modulate myogenic vasoconstriction (1663), although genetic deletion of KCNQ3, 4, or 5 did produce constriction
of mouse mesenteric arteries or isolated perfused kidneys
(1294).
The myogenic tone of skeletal muscle arterioles results from
an interaction between Ca2⫹ entry through L-type VOCC
secondary to pressure-induced membrane depolarization
and CICR and Ca2⫹ mobilization mediated by RyR. BKCa
modulation of EM played only a small role in limiting myogenic vasoconstriction in this vascular bed (827). However,
inhibition of RyRs in mouse pressurized mesenteric arteries
increased myogenic constriction, presumably by reducing
BKCa activity to favor membrane depolarization and Ca2⫹
entry through VOCCs (836).
In summary, most evidence suggests that BKCa channels are
normally quiescent in the renal microcirculation and do not
respond to changes in RPP or limit the myogenic response,
in contrast to their central role in the cerebral circulation.
However, 20-HETE is reported to enhance myogenic constriction by inhibiting BKCa activity in some situations. Activation of other K⫹ channels that hyperpolarize the EM
also can inhibit myogenic responsiveness under specific experimental conditions such as hypoxia, whereas inhibition
of BKCa channels in some settings can depolarize VSMCs
and favor vasoconstriction. MD-TGF responses depend on
ROMK channels in MD that mediate K⫹ recycling after
reabsorption by NKCC-2 (1312).
C. Sodium Channels
Evidence relating to the proposal that ENaC subunits are
expressed on VSMCs of preglomerular vasculature and
function as mechanosensors in the myogenic response was
discussed in section IIIB. The VSMC plasma membrane
Na⫹/Ca2⫹ exchanger (NCX1) normally promotes Ca2⫹ entry and Na⫹ extrusion (1655), in contrast to the heart
where NCX1 primarily mediates Ca2⫹ extrusion (327).
Normally, three Na⫹ are exchanged for one Ca2⫹ (119).
NCX contributes to the myogenic response by favoring
Ca2⫹ entry both in nonrenal vessels and also in the renal
circulation where it enhances vasoconstrictor responses.
Ca2⫹ entry via NCX1 is implicated in pressure-induced
myogenic constriction in mouse mesenteric and hindlimb
arteries (713, 1655), rat cremaster first-order arterioles
(150 ␮m) (1206), and rat posterior cerebral arteries (771).
Reducing extracellular Na⫹ around isolated cremaster
muscle arterioles promoted NCX1 activity and Ca2⫹ entry
to enhance myogenic vasoconstriction (1206), whereas decreasing the activity of the VSMC NCX impaired arteriolar
myogenic reactivity (1206). Knockout of NCX1 in VSMCs
reduced vasoconstriction elicited by PE, high KCl, PP, or
L-type Ca2⫹ channel currents in mouse mesenteric arteries
and lowered BP (1655). Myogenic and ANG II responses of
mesenteric arteries were blunted in mutant mice lacking the
NCX1 in VSMCs (1655, 1660) accompanied by attenuated
Ca2⫹ entry and myogenic responses (1010, 1655).
A PKC regulated NCX1 in the afferent arteriole usually
operates in the “reverse” mode with Ca2⫹ entering VSMCs
down its concentration gradient to drive Na⫹ efflux and
promotes vasoconstriction (120, 430, 1079). Reducing extracellular [Na⫹] in the isolated perfused kidney promoted
Ca2⫹ entry into afferent arteriolar VSMCs via NCX to
increase [Ca2⫹]i (1078, 1079) and RVR (1335). Inhibition
or genetic deletion of NCX1 reduced the afferent arteriolar
[Ca2⫹]i responses and the vasoconstriction to ANG II (402,
1660).
The expressions of NCX1, sarcoplasmic reticular Ca2⫹ATPase-2 (SERCA2), and TRPC6 in VSMCs are inversely
related to the activity of the ␣2-subunit of Na⫹-K⫹-ATPase
(120), whose reductions in mesenteric arterial VSMCs have
been linked to increased Ca2⫹ signaling and augmented
myogenic- and PE-induced vasoconstriction mediated by
IP3 release of Ca2⫹ from the sarcoplasmic reticulum and
Ca2⫹ entry through SOC channels (119). Mesenteric arteries expressing 50% of the normal amount of the ␣2-subunit
of the Na⫹ pump had augmented myogenic contraction
(1654). VSMC NCX1, SERCA2, and TRPC6 were overexpressed in fourth-order mesenteric arteries of Milan genetically hypertensive rats which had exaggerated myogenic
responses (905).
However, NCX can operate in the “forward” mode in
VSMCs, thereby mediating Na⫹ influx in exchange for
Ca2⫹ efflux, for example, in the vasculature of the isolatedperfused kidney (1335) or skeletal muscle arteries where
blockade of NCX enhanced myogenic tone, presumably by
reducing Ca2⫹ extrusion (634). NCX activity in VSMC can
be inhibited by oxidative stress that also increased [Ca2⫹]i
(1505).
Thus Na⫹/Ca2⫹ exchange via NCX1 has variable effects
depending on whether it functions in the forward or reverse
mode. It typically functions in the reverse mode in renal
afferent arteriolar VSMCs to facilitate Ca2⫹ entry down its
concentration gradient, thereby expelling Na⫹ and promoting myogenic contractions. Its activity is linked to Na⫹-K⫹ATPase via change in the ␣2 subunit which can account for
the enhanced myogenic tone, and perhaps some of the hypertension, in the Milan genetically hypertensive rat.
V. CALCIUM SIGNALING PATHWAYS
INVOLVED IN AUTOREGULATORY
RESPONSES
An abrupt increase in RPP in mouse microperfused outer
cortical afferent arterioles increases [Ca2⫹]i within seconds,
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439
RENAL AUTOREGULATORY MECHANISMS
followed by a sharp decline to a half-maximal level (865),
whereas the juxtamedullary afferent arteriole has a rather
more sustained rise in [Ca2⫹]i (1637). Both preparations
demonstrate a maintained myogenic contraction despite declining [Ca2⫹]i, indicating increased sensitivity of the contractile machinery to [Ca2⫹]i. There are comprehensive reviews on VSMC Ca2⫹ signaling during generalized myogenic vasoconstriction (169, 301, 302, 478, 614, 1001,
1249, 1329) and its role in modulating renal vascular microcirculatory responses (49, 1249, 1280). Also recommended are excellent mathematical models of renal autoregulation and the Ca2⫹ dynamics of the myogenic response
of the afferent arteriole (228, 374, 395, 628, 805, 1350,
1351, 1614). The models incorporate ionic transport and
cell membrane potential with contraction dynamics of the
afferent arteriolar VMSC.
A. Calcium Entry and Mobilization
Vasoconstriction results from a combination of increased
[Ca2⫹]i and augmented Ca2⫹ sensitivity (FIGURE 8). Intracellular Ca2⫹ signaling involves both Ca2⫹ entry across the
plasma membrane and Ca2⫹ release from intracellular sarcoplasmic reticular stores (1329, 1625, 1630). Ca2⫹ entry
into preglomerular VSMCs can be mediated by L-type and
perhaps T-type VOCCs, voltage-independent receptor-operated channels (e.g., TRPCs, TRPMs, and GPCR-coupled
channels), and SOC. GPCRs normally recruit more than
one type of cation channel. Both the sustained myogenic
tone and the MD-TGF-mediated vasoconstriction are
highly dependent on membrane depolarization and Ca2⫹
entry through L-type VOCC. As discussed in later sections,
Ca2⫹ sensitivity of the contractile proteins is primarily regulated by PKC and Rho/Rho kinase.
The mechanisms underlying mechanosensation and initiation of the myogenic response vary among vascular beds,
but usually involve an initial depolarization of the plasma
membrane that activates Ca2⫹ entry through L-type
VOCCs that leads to activation of myosin light-chain phosphorylation and vasoconstriction. A decreased intraluminal
pressure has the opposite effects, thereby resulting in vasodilation. Removal of extracellular Ca2⫹, or inhibition of
L-type VOCC activity, abolishes the myogenic response.
Mechanotransduction is a key triggering process, but the
details are poorly understood. Mechanosensitive initiating
elements include ion channels (e.g., TRPC, ENaC) or extracellular proteins (e.g., integrins). Pressure activation of
ENaC or nonselective cation TRPC channels may cause
depolarization by favoring Na⫹ entry. There is considerable
regional diversity in subsequent Ca2⫹ signaling and Ca2⫹
sensitivity of the actin/myosin contractile apparatus responsible for regulation of local blood flow and capillary hydrostatic pressure.
The myogenic response of the afferent arteriole is initiated
by depolarization of its VSMCs which, in turn, activate
440
L-type VOCCs to allow Ca2⫹ entry. Although the precise
mechanisms responsible for the initial depolarization of the
plasma membrane are unclear, they may entail the opening
of a cation channel to allow Na⫹ or Ca2⫹ entry, the opening
of a Cl⫺ channel to permit Cl⫺ exit, or the closing of K⫹
channels to prevent K⫹ efflux. All of these possibilities are
under current investigation.
Little is known about the role of Ca2⫹ mobilization resulting from Ca2⫹-induced Ca2⫹ release (CICR) from the sarcoplasmic reticulum following stimulation by IP3 and RyRs
and less still about Ca2⫹ release from lysosome-like acidic
vesicles (49, 1456). Ca2⫹ entry through VOCCs can amplify CICR from the sarcoplasmic reticulum therby enhancing arteriolar contraction (401, 1457). Depletion of sarcoplasmic reticular Ca2⫹ stores in nonrenal vessels can promote Ca2⫹ entry through TRPC or Orai channels. Orai
channels on VSMCs mediate Ca2⫹ entry by Ca2⫹ releaseactivated Ca2⫹ channels after activation a stromal interaction molecule (STIM) protein linking the sarcoplasmic reticulum to the plasma membrane (1390, 1482, 1658). Although renal resistance arterioles have store-operated Ca2⫹
entry channels (397, 398, 925, 1448, 1616), their molecular
identity is not yet known and their role in regulating myogenic or MD-TGF mediated autoregulatory tone has not
been studied.
1. Calcium entry through VOCCs
The renal preglomerular arteries and arterioles expressed
mRNA for three types of VOCCs of the L (Cav 1.2), T (Cav
3.1 and 3.2), and P/Q (Cav 2.1) subtypes (35, 558, 560,
595, 633). Depolarization of the plasma membrane led to
Ca2⫹ entry through L-type VOCCs in the afferent arteriole,
which was blocked by the dihydropyridine Ca2⫹ channel
blockers (CCB) (191, 558, 935). The depolarization mechanism adapts over time. Thus 2 days of hypertension enhanced expression of the ␣1c-subunit of the Cav1.2 Ca2⫹
channel in the rat main renal artery (1175), which may
contribute to sustaining the vasoconstriction. Increasing the
transmural pressure of a dog cortical radial artery from 20
to 120 mmHg reduced the EM from ⫺57 to ⫺38 mV and
increased the contractile tone of its VSMCs (562), whereas
increasing the luminal pressure from 60 to 100 and then to
145 mmHg reduced the EM from ⫺45 to ⫺38 and to ⫺33
mV, respectively (920). Pressurized afferent arterioles in the
HNK preparation had a resting EM of ⫺40 to ⫺45 mV that
was close to the activation threshold of ⫺30 mV of L-type
VOCCs (928, 1388).
Increasing the luminal pressure from 40 to 140 mmHg in
cerebral arteries of WKY rats and cats reduced the EM of
VSMCs from ⫺57 to ⫺41 mV, followed by an action potential spike and a contraction (561, 564). Harder and associates (466, 563) presented evidence that increased cerebral transmural pressure increased 20-HETE that activated
PKC which inhibited BKCa channels. This depolarized the
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CARLSTRÖM ET AL.
VSMCs and activated L-type VOCCs to increase [Ca2⫹]i.
Such a chain of events mediated autoregulation of cerebral
blood flow (466, 563).
Ca2⫹ entry through L-type VOCCs is required for renal
myogenic and MD-TGF autoregulatory adjustments of the
preglomerular vasculature (FIGURE 3D). Autoregulation is
abolished following blockade of VOCCs, or removal of
extracellular Ca2⫹ from the isolated perfused kidney of the
dog (1106, 1108, 1110, 1112, 1120) or rat (1285, 1323) or
the kidney of the dog (760, 1069, 1089, 1120) or the rat in
vivo (102, 499, 646, 749, 852). CCBs prevent preglomerular myogenic responses of isolated cortical radial arteries or
afferent arterioles of the dog (562) or rat or mouse (861,
890) or rabbit (52). Ca2⫹ entry via VOCCs in the renal
vasculature is essential also for autoregulatory adjustments
of the JMN preparation (192, 194, 200, 201, 688, 1020,
1281, 1437) and the chronic HNK model (586, 587, 593,
929, 931, 1446). CCBs eliminated the MD-TGF response in
the JMN (194, 201) and the isolated JGA preparations (82).
Pharmacological studies implicated T-type VOCCs in the
myogenic response of afferent arterioles (407). However,
recent patch-clamp studies of voltage-activated Ca2⫹ currents indicated that freshly isolated VSMCs of the rat afferent arteriole have a high density of L-type channels, but do
not express functionally active T-type VOCCs (1388).
Myogenic tone in the perfused hindlimb was attributed exclusively to Ca2⫹ entry through Cav l.2 L-type channels
(1024), whereas both L- and T-type VOCCs participate in
the myogenic response in rat cerebral arteries (4, 576).
The regulation of CaV1.2 L-type VOCC trafficking has
been studied in cerebral arteries where insertion of activated
CaV1.2 into the cell membrane enhanced basal and myogenic tone (1058). Stretch-induced influx of Ca2⫹ generated
IP3 and released Ca2⫹ from the sarcoplasmic reticulum.
Increased myogenic tone and elevated [Ca2⫹]i were greater
in rat brain parenchymal arterioles than in middle cerebral
arteries (264), likely because of a higher density of VOCC
and a lower BKCa activity.
PI3K/Akt signaling promoted voltage-dependent trafficking
of Ca2⫹ channels to the plasma membrane that increased
Ca2⫹ influx via L-type VOCC and thereby was involved in
the myogenic response in mouse second-order mesenteric
arteries (197, 910). Genetic knockdown of Dicer for 5– 6
wk to reduce the global role of microRNAs (miRNAs) lowered BP and myogenic tone in mesenteric arteries by reducing PI3K/Akt signaling and L-type VOCC activity (specifically the ␣2␦1 subunit) (101). Interestingly, myogenic tone
was restored by stimulation of PI3K signaling by short-term
ANG II exposure and by activation of L-type VOCC channels by BAY K8644. Thus noncoding miRNAs have been
identified as regulators of vascular contractility and the
myogenic response. Future studies are warranted to inves-
tigate the role of this novel mechanism in renal autoregulatory responses.
In summary, L-type VOCCs play an essential role in the
transmembrane Ca2⫹ flux that is required to initiate a myogenic contraction, but the role of T-type VOCCs remains
controversial and likely depends on the experimental conditions.
2. Calcium mobilization mediated by IP3Rs
Ca2⫹ is stored in the sarcoplasmic reticulum in VSMCs at
high millimolar concentrations from where it can be released by either IP3 or ryanodine acting on specific receptors/channels (FIGURE 8). Type 1 IP3Rs were expressed on
VSMCs of intrarenal arteries, afferent arterioles, and glomerular mesangial cells, and type 3 IP3Rs were expressed on
VSMCs and mesangial cells (596, 1018). The mRNAs for
IP3 type 1 and 2 receptors have been identified in VSMCs of
small renal arteries (1197).
Increased PP in renal arteries and afferent arterioles activated PLC which enhanced the production of IP3 and subsequent Ca2⫹ mobilization (1059). On the other hand, inhibition of IP3 receptor-mediated [Ca2⫹]i mobilization in
the dog perfused kidney did not affect steady-state RBF
autoregulation, although it attenuated NE-induced renal
vasoconstriction (1111). Autoregulatory adjustments of afferent arterioles of JMN were attenuated by reducing Ca2⫹
mobilization from internal stores (688). Inhibition of Ca2⫹
uptake into the sarcoplasmic reticulum by Ca2⫹-ATPase
prevented myogenic contraction of afferent arterioles in the
JMN preparation (688), but the relative involvement of
IP3Rs and RyRs in release of stored Ca2⫹ was not investigated. Inhibition of PLC and thus of IP3 generation in the
cortical radial artery attenuated myogenic contractions by
50%, but this was limited to the proximal arterial segments
(1447). Thus there are different mechanisms for mobilization of Ca2⫹ for the myogenic response along the cortical
radial artery of JMN and perhaps the preglomerular vasculature in general. Nevertheless, Ca2⫹ mobilization contributes importantly to the myogenic mechanism, and perhaps
also to MD-TGF in the renal microvasculature of at least
some nephron populations.
The myogenic response of VSMCs can be engaged after
activation of PLC, generation of IP3, and activation of IP3sensitive receptors on the sarcoplasmic reticulum to release
Ca2⫹ from internal stores. Alternatively, DAG produced by
PLC in VSMCs can activate ion channels including TRPC6
in the plasma membrane to increase [Ca2⫹]i by transmembrane flux. Stretch- or pressure-induced recruitment of
GPCR may increase PLC production of IP3 and DAG during the myogenic response (1137). Inhibition of PLC in
nonrenal vessels hyperpolarized the EM from ⫺44 to ⫺53
mV, diminished Ca2⫹ entry, reduced [Ca2⫹]i, and attenuated the myogenic response (301, 724). The PLC/DAG sig-
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441
RENAL AUTOREGULATORY MECHANISMS
naling pathway participated in myogenic responses of human subcutaneous arteries (266). DAG may activate
TRPC6 channels to depolarize the plasma membrane to
initiate a rise in [Ca2⫹]i via VOCCs. However, IP3 of skeletal muscle arterioles did not influence Ca2⫹ release during
myogenic responses (827). The specific role of TRPC channel activation by DAG in the myogenic response of the renal
microcirculation is poorly understood and warrants further
investigations.
3. Calcium mobilization mediated by RyRs and
cADP-ribose
Ca2⫹-induced Ca2⫹ release (CICR) of VSMCs refers primarily to activation or sensitization of RyRs, in particular
RyR2 and RyR3, to mobilize intracellular Ca2⫹, thereby
releasing more Ca2⫹ from the sarcoplasmic reticulum (49).
Activation of GPCRs is linked to ADP-ribosyl cyclase that
generates cADP-ribose that sensitizes the RyR to mobilize
Ca2⫹ and enhance vasoconstriction (FIGURE 8) (49, 399,
400, 1456, 1457). This is a relatively newly recognized
VSMC signaling pathway. Ca2⫹ entry through L-type
VOCCs also enhances RyR-mediated Ca2⫹ mobilization
and renal vasoconstriction (401, 1457), thereby implicating
cADP-ribose and RyR in Ca2⫹ signaling in the myogenic
response especially in the maintenance phase. A similar
mechanism may explain the coupling of RyRs to stretchactivated cation channels (1032).
O2⫺
produced in VSMCs by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase may link activation of
GPCRs to stimulation of ADP-ribosyl cyclase production of
cADP-ribose that increases Ca2⫹ signaling and renal vasomotor tone (399, 400, 1651). Stretch of afferent arterioles
stimulated NOX-2/p47phox-dependent production of O2⫺
that enhanced the strength of the myogenic response (864,
866). Moreover, O2⫺ generated by NOX-2 in stretched cardiac myocytes and pulmonary VSMCs sensitized RyRs to
enhance [Ca2⫹]i (349, 1201). The extent to which RyRs
mediate Ca2⫹ mobilization in renal afferent arterioles, and
their involvement in the myogenic response, requires further investigation.
Afferent arteriolar vasomotion following activation of Ltype VOCCs and Ca2⫹ entry, which is an index of intrinsic
myogenic tone, was prevented by inhibition of RyRs, but
not by inhibition of IP3Rs (1443). In fact, caffeine enhanced
the fast oscillations in vasomotor tone, indicating that Ca2⫹
entry via L-type VOCCs was reinforced by Ca2⫹ mobilization by RyRs (1443).
An increase in luminal pressure in cerebral arteries induced
Ca2⫹ sparks that were generated by RyRs acting on the
sarcoplasmic reticulum adjacent to the plasma membrane
(720, 919). The local increase in [Ca2⫹]i activated BKCa in
the VSMC plasma membrane to hyperpolarize the cell, and
thereby inactivate L-type VOCCs. As a result, there was a
442
reduced Ca2⫹ entry that limited [Ca2⫹]i and opposed myogenic tone (16, 720, 810). The same sequence of events was
reported in mesenteric arteries of one study (836), whereas
myogenic tone of mesenteric arterioles was independent of
Ca2⫹ mobilization in another (1577).
Blockade of RyRs in VSMCs of cremaster muscle feed arteries by ryanodine or tetracaine inhibited Ca2⫹ sparks and
Ca2⫹ waves, BKCa activity, global [Ca2⫹]i, and myogenic
tone. On the other hand, blockade of RyRs in smaller cremaster muscle arterioles did not affect Ca2⫹ signaling or
vascular tone (1596, 1597). In fact, Ca2⫹ mobilization mediated by IP3R enhanced global [Ca2⫹]i and myogenic tone
in both vessel types without affecting Ca2⫹ sparks. Other
studies reported that activation of RyRs increased global
[Ca2⫹]i, Ca2⫹ entry through L-type VOCC, and myogenic
tone in isolated rat skeletal muscle gracilis arterioles but not
in mesenteric arterioles (1576, 1577). Depletion of sarcoplasmic reticulum Ca2⫹ stores by ryanodine in isolated skeletal muscle gracilis arterioles slowed the development of
myogenic tone (178). Thus there are striking regional differences in the roles of RyRs in modulating Ca2⫹ signaling
and myogenic responses. RyRs in skeletal muscle arterioles
mobilize Ca2⫹ and induce myogenic constriction, whereas
RyRs in cerebral arteries induce Ca2⫹ sparks that activate
BKCa and inhibit myogenic tone.
As discussed in section IVB, BKCa channels in the renal
preglomerular vessels generally are inactive. Moreover,
global Ca2⫹ mobilization by RyRs lead to marked increases
in [Ca2⫹]i and pronounced vasoconstriction rather than the
vasorelaxation anticipated from activation of BKCa (49).
However, little is known about the function of small Ca2⫹
sparks in the renal microcirculation except that they likely
are triggered by integrin deformation.
Fibronectin in the extracellular matrix surrounding VSMC
is a natural ligand for ␣5␤1-integrin whose mechanical distortion in the rat afferent arteriole can activate Ca2⫹ release
via RyRs on the sarcoplasmic reticulum and trigger local
Ca2⫹ sparks, global Ca2⫹ mobilization, and contraction
2⫹
(FIGURE 8) (64, 214). ␣5␤1 Integrins also initiated Ca
waves that propagated along preglomerular VSMCs (214).
Myogenic constriction was inhibited by integrin-specific
binding peptides or by blockade of Ca2⫹ mobilization by
RyRs. Integrins in pulmonary VSMCs activated ADP-ribosyl cyclase to produce cADP-ribose that activated RyR and
released Ca2⫹ from the sarcoplasmic reticulum (1500). Repetitive cycles of RyR-mediated Ca2⫹ mobilization and
Ca2⫹ entry through plasma membrane SOC of vasa recta
pericytes may be responsible for oscillations in membrane
currents and global [Ca2⫹]i (1443, 1656).
In summary, pressure-induced membrane depolarization
and Ca2⫹ entry through VOCCs are fundamental to the
arteriolar myogenic response. The initial mechanisms me-
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CARLSTRÖM ET AL.
diating mechanotransduction and triggering the depolarization of the plasma membrane of VSMCs are poorly understood. Ca2⫹ sensitivity of actin/myosin contractile complex
is central to the maintenance phase of myogenic contractions. RyR-mediated Ca2⫹ sparks and BKCa activation can
oppose myogenic vasoconstriction in some vascular beds
such as the cerebral circulation, whereas RyR-induced
CICR and amplification of [Ca2⫹]i can potentiate myogenic
constriction in other circulations, likely including the afferent arteriole. Increased [Ca2⫹]i may initiate membrane depolarization by activating ClCa channels or by offsetting the
effects of membrane hyperpolarization by activation of
BKCa channels. The precise role of RyR-mediated Ca2⫹ mobilization in the renal myogenic response requires further
investigation, as does its participation in MD-TGF activity.
Overall, CICR provides an important amplification of the
increase in [Ca2⫹]i initiated by Ca2⫹ entry through L-type
VOCCs.
B. Mechanisms Increasing Calcium
Sensitivity
Although an elevated [Ca2⫹]i is a key requirement for initiating the myogenic response in arteries and arterioles,
[Ca2⫹]i may wane over time despite a sustained myogenic
vasoconstriction (290). This dissociation implies a change
in the balance between the MLCK and MLCP and the phosphorylation state of the actin/myosin proteins to favor contraction (59, 1328). The Ca2⫹ sensitivity of the contractile
apparatus of VSMCs is defined by the amount of active
phosphorylated 20-kDa MLC (MLC20) at a given level of
[Ca2⫹]i and is regulated by PKC and the Rho/Rho kinase
(FIGURE 8) (1392). Increased vascular transmural pressure
facilitated Ca2⫹ sensitization and contraction mediated by
the RhoA/Rho-associated kinase pathway that inhibited
MLCP by phosphorylating the MLCP targeting regulatory
subunit (MYPT1) and/or the 17-kDa PKC (743). The 17kDa form of PKC in VSMCs inhibited MLCP that potentiated protein phosphatase 1 inhibitor protein (CPI-17). This
increased MLC20 phosphorylation and thereby favored
VSMC contraction. However, other mechanisms contribute to Ca2⫹ sensitivity. Thus PKC in VSMCs also phosphorylates MLC20 via MLCK that magnifies Ca2⫹-induced actin-myosin interaction and force development. Actin polymerization enhanced connections between the actin
cytoskeleton, the plasma membrane, and the extracellular
matrix which promoted force transmission (1548). Both
cytochrome P-450 – 4A/20-HETE and ROS enhanced Ca2⫹
sensitivity (1328). Endothelial factors such as ET-1 and
TxA2 also increased Ca2⫹ sensitivity and myogenic vasoconstriction in gracilis muscle arterioles (1502). Inhibition
of PKC, but not the cytochrome P450 inhibitor 17-ODYA,
in isolated arterioles from rat skeletal muscle reduced myogenic tone (63). Moreover, smoothelin-like proteins have
been implicated in VSMC contractility and vascular adaptations during hypertension. Smoothelin-like 1 protein at-
tenuated the myogenic response in cerebral arteries possibly
by inhibiting the expression of MYPT1 (1496).
Thus Ca2⫹ sensitivity is a complex process involving PKC
and Rho/Rho kinase signaling and other mechanisms that
regulate the phosphorylation state of the contractile proteins. These processes play an important role in myogenic
constriction.
1. PKC
PP and GPCR agonists stimulate phospholipid turnover
that generates DAG that in turn activates PKC (FIGURE 8).
Translocation of PKC to the plasma membrane triggered a
cascade of signaling that enhanced Ca2⫹ sensitivity (1275).
Both the Ca2⫹-dependent PKC␣ and the Ca2⫹-independent
PKC⑀ enhanced the sensitivity of myofilaments to [Ca2⫹]i,
whereas the cytoskeletal PKC␦ and the nuclear PKC␨ were
not effective (324). Stretch of rabbit basilar arteries triggered translocation of PKC␣ (but not PKC⑀) and RhoA
from the cytosol to the plasma membrane which increased
phosphorylation of MLC and contributed to the Ca2⫹ sensitivity and the contractile response (1634).
PKC is considered crucial for renal vasoconstriction produced by ANG II and ET-1 (22, 68, 1265, 1322, 1659). The
myogenic tone of afferent arterioles of the rat HNK preparation was mediated in part by the basal level of PKC that
enhanced Ca2⫹ sensitivity, independent of voltage-dependent activation (802).
Inhibition of PKC attenuates myogenic tone in basilar arteries (1634), cerebral arteries (63, 474, 603, 725, 855,
1136, 1136, 1164), coronary arteries (324, 1006), mesenteric arteries (380), cremaster and skeletal muscle arterioles
(63, 977), and subcutaneous arteries (266). Inhibition of
PKC in skeletal muscle arteries prevented a myogenic response to a PP increase without affecting the increase in
[Ca2⫹]i (768). This was specific for PKC␣ in coronary arteries (324). Pressure-induced constriction of cerebral arteries was dependent on increased Ca2⫹ sensitivity due to PKC
and Rho kinase (63, 603, 855).
In summary, PKC activation is a central component of Ca2⫹
sensitivity and the myogenic response in most arteries studied, including the renal preglomerular vessels.
2. Rho/Rho-kinase
As mentioned above, Rho kinase can enhance contractility
by inhibiting MLC phosphatase by targeting MYPT1 (FIGURE 8). Mechanical stimulation of VSMCs translocates the
GTPase Rho and its associated Rho kinase to caveolin-1 in
the plasma membrane. The myogenic response was enhanced by RhoA/Rho-kinase phosphorylation that inactivateed MLCP and augmented Ca2⫹ sensitivity (350). Inhi-
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RENAL AUTOREGULATORY MECHANISMS
bition of this system, or disruption of caveolin-1, reduced
myogenic force in mesenteric and ophthalmic arteries (380,
694). Rat cerebral artery myogenic tone depended on the
independent effects of Rho-kinase and PKC mediating increased Ca2⫹ sensitivity, but Rho kinase predominated
(694, 725, 855). The myogenic response of gracilis and
cremaster muscle arteries involved Rho-kinase and PKCevoked Ca2⫹ sensitization leading to inhibition of MLCP
and cytoskeletal reorganization of actin polymerization
(1027). Membrane depolarization in pulmonary artery
VSMCs generated O2⫺ that activated RhoA and led to Ca2⫹
sensitization (1233). RhoA activation and interaction with
caveolin-1 were critical for pressure-induced myogenic tone
in rat mesenteric resistance arteries (350).
Juxtamedullary preglomerular arterioles expressed Rho-kinase ␣ and ␤ (691), whose inhibition completely abolished
autoregulation (691), thereby implying inhibition of both
myogenic and MD-TGF mechanisms. Indeed, recent work
showed that Rho-kinase participates in afferent arteriolar
vasoconstriction mediated by both myogenic and MD-TGF
mechanisms in response to elevated RPP in the superficial
cortex of WKY rats (632). Rho kinase in the rat HNK
preparation participated in the myogenic vasoconstriction
of cortical radial arteries and afferent arterioles to changes
in increased PP, ANG II, and reduced EM (1259, 1358).
Inhibition of Rho-kinase blunted pressure-induced myogenic tone and depolarization-induced constriction of isolated afferent arterioles (1054) and also almost abolished
the dynamic RPP-RBF transfer functions representative of
both the myogenic and MD-TGF responses (1358).
In summary, activation of Rho/Rho-kinase is a quantitatively important step in increasing the Ca2⫹ sensitivity that
maintains or enhances both the myogenic and MD-TGF
autoregulatory mechanisms in the kidney.
VI. MODULATING AGENTS
The myogenic response of renal (915) and nonrenal (301)
vessels was generally intrinsic to their VSMCs and independent of endothelial input. Thus myogenic constriction
clearly was triggered within VSMCs, although it could be
modulated by various endothelial factors. Despite the constancy of afferent arteriolar blood flow during increased PP
by effective autoregulatory adjustments in vascular resistance, the narrowed vascular lumen will increase vessel wall
shear stress that could activate endothelial pathways producing vasoactive agents. For example, NO was released by
eNOS in response to ANG II (699, 1160), ET-1 (701, 757),
or shear stress (696, 747, 1184). Other potential modulators of myogenic tone in the kidney can originate from
structures involved in MD-TGF or CT-GF with signaling
from MD or CT tubular cells (FIGURE 6).
444
A. ANG II
JG granular cells in the terminal afferent arteriole increase
renin release and thereby ANG II production (FIGURE 1) in
response to reduced luminal pressure at the end of the afferent arteriole, low NaCl delivery to the MD, or increased
sympathetic nerve activity activation of ␤-adrenoceptors
(204, 846). Proximal tubular and CD cells also contribute
to intrarenal renin and ANG II generation (812, 1076).
Most studies have concluded that the RAS was not essential
for efficient steady-state autoregulation of RBF. ANG II
infusion, or inhibition of AT1 receptors or ACE, did not
modify highly efficient whole kidney autoregulation in dogs
(5, 27, 90, 97, 103, 194, 548, 550, 755, 1003, 1047, 1072,
1171, 1261) or rats (45, 329, 750) even during low-salt diet
producing strong activation of the RAS and did not usually
affect the lower limit of RBF autoregulation. ANG II also
did not affect renal medullary blood flow autoregulation
(288). However, ANG II was more important in steadystate autoregulation of the GFR than the RBF (488, 550,
774, 1261), especially at lower RPP, most likely by maintaining efferent arteriolar tone. However, a few studies have
reported that the RAS was essential for effective steadystate autoregulation of RBF and GFR (764, 1479). Moreover, autoregulation of isolated perfused rats kidneys was
improved by ANG II (523).
Micropuncture studies of superficial nephrons demonstrated that MD-TGF responses were enhanced by ANG II
(133, 1012, 1308, 1309) and diminished by blockade of
ACE (133, 648, 1189, 1422, 1495), or AT1 receptors (781,
1309, 1590), or by deletion of the genes for ACE or AT1A
receptors (582, 1310, 1318, 1481). AT1 receptors may
modulate MD-TGF responses by actions on the vasculature
or on NKCC2 cotransport activity in MD cells (829, 1012,
1556). These effects were countered by NO production by
MD nNOS (656).
One mechanism of MD-TGF enhancement by ANG II is
synergistic potentiation of the actions of adenosine on the
afferent arteriole (440, 556, 862, 863, 1159, 1480, 1580).
Thus ANG II appears to be an important modulator of
MD-TGF activity, but its presence or absence usually has
little impact on highly efficient steady-state autoregulation
of RBF, at least during the plateau phase.
The effects of ANG II on the myogenic mechanism in the
kidney are controversial. ANG II contracted the afferent
arteriole of the JMN preparation without affecting its autoregulatory response (690). However, low levels of ANG II
enhanced the myogenic response in the HNK preparation
by potentiating PKC-induced increases in Ca2⫹ sensitivity
(802). ANG-(1–7) had no effect on the myogenic tone of
preglomerular vessels in the HNK preparation (1524).
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CARLSTRÖM ET AL.
Short-term infusion of ANG II at pressor rates caused renal
vasoconstriction without major effects on the myogenic response, the MD-TGF, or the third mechanism analyzed by
time-dependent changes in RVR following a rapid, step
increase in RPP (750, 755). ACE inhibition has no effect on
the myogenic response, and the MD-TGF was slightly attenuated (755). Short-term administration of vasoconstrictor amounts of ANG II to the conscious dog slightly augmented the admittance gain of the transfer functions representing the myogenic and MD-TGF responses, but without
affecting their relative contributions (755). Prolonged infusions of ANG II, but not PE, into conscious or anesthetized
rats potentiated the admittance gain of the myogenic response but not the MD-TGF (1193). Whereas ANG II
slightly increased the slope of the admittance gain reduction, consistent with increased strength of the myogenic
mechanism, it did not modify the signature resonance peak
of the myogenic mechanism (at ⬃0.23 Hz), which is an
indicator of the speed of contraction. The ANG II effect is
attributed to activation of AT1 receptors rather than increased RPP. Other frequency analysis studies indicated
that increased endogenous ANG II enhanced the myogenic
and MD-TGF responses in rats (329, 597), but reduced
ANG II activity produced by high salt diet had little effect
(1271, 1273). Other studies employing dynamic frequency
analysis reported that acute hypertension produced by PE
does not affect the myogenic or the MD-TGF mechanism in
Wistar (1358) and Brown-Norway (BN) rats (1570).
Staircase changes in RPP can produce hysteresis loops
where there are different RVR responses to increases versus
decreases in RPP in the anesthetized (284) and conscious rat
(423). Autoregulation curves for RBF had a lower plateau
level when measured during sequential increases compared
with subsequent decreases in RPP. This was attributed to
activation of the RAS by hypotension. The outcome was
that the RAS enhanced RVR at low RPP where it engaged
the MD-TGF for RBF autoregulation (284).
Early micropuncture studies in the rat reported reductions
in RPP below the normal lower limit of autoregulation
abolished MD-TGF, but this was slowly restored by ANG II
generation after 20 – 60 min of maintained hypoperfusion
(1343). The increased RAS activity reduced the lower limit
for RBF autoregulation (284, 624, 707, 1397).
The putative third mechanism may be modulated by ANG
II (1342). ANG II can enhance CT-GF leading to a paradoxical dilation of the afferent arteriole by activating ENaC
and stimulating Na⫹ reabsorption in the CT (1227).
Sex differences have been reported for expression of AT1
and AT2 receptors and their functional impact on renal
autoregulation, MD-TGF, and pressure-natriuresis. Kidneys of female rats express a higher density of vasodilator
AT2 receptors that can increase the lower limit of RPP for
RBF autoregulation and shift the pressure-natriuresis relation to excrete more Na⫹ at a lower RPP (619). Augmented
AT2 receptor signaling in female rats also accounted for a
blunted effect of ANG II to enhance MD-TGF (156).
In summary, ANG II is a potent vasoconstrictor of the afferent and efferent arterioles. Reductions in RPP release
renin and generate ANG II within the kidney which preferentially activates AT1 receptors on the efferent arteriole,
thereby maintaining PGC and GFR. This accounts for the
particular effect of ANG II in maintaining autoregulation of
GFR, relative to RBF, at reduced RPP. Additionally, agonist-independent, stretch activation of AT1 receptors can
interact with TRP channels as mechanosensors (see sect.
IIIC). ANG II clearly magnifies MD-TGF responses, but
most studies suggest a rather weak effect on the myogenic
response. Yet, although the individual components of renal
autoregulation may be modified by acute ANG II, this generally does not cause major changes in overall steady-state
RBF autoregulation. The exception is that ANG II generated by hypotension can modulate the lower limit of PP
steady-state autoregulation, perhaps through its ability to
enhance MD-TGF activity. As noted in section VIIB5,
chronic ANG II infusion causes hypertension, but the effects on the efficiency of RBF autoregulation are inconsistent.
B. Eicosanoids
Vascular production of vasodilatory PGs such as PGE2 and
PGI2 commonly buffer the actions of vasoconstrictor agents
(671), but renal hemodynamics also are modulated by vasoconstrictor PGs and by tubular production of eicosanoids. A reduction in RPP reduced the release of PGE2
and PGI2 from the kidney. However, PGs did not affect
steady-state RBF autoregulation in salt-replete rats (422) or
dogs (1531) or autoregulation of the PGC in superficial
nephrons of normal Munich-Wistar rats (1167). Moreover,
arachidonate metabolites of COX or cytochrome P-450
were not required for steady-state RBF autoregulation in
isolated perfused kidneys of the dog (763, 1107) or rat
(1285) or for myogenic contractions of afferent arterioles
(588, 747).
Nevertheless, other studies have implicated PGs under certain circumstances. Thus the poor autoregulation of papillary blood flow in the rat kidney was improved by COX
inhibition (1127), while whole kidney RBF autoregulation
was slowly enhanced following COX inhibition (833). Efficient autoregulation of GFR in superficial nephrons depended on COX metabolites contributing to MD-TGF
(1313). COX products also participated in conventional
MD-TGF-mediated adjustments of afferent arteriolar tone.
Micropuncture studies of superficial nephrons demonstrated that COX inhibition reduced MD-TGF sensitivity to
changes in tubular flow (1034, 1307, 1319), but this was
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RENAL AUTOREGULATORY MECHANISMS
restored by tubular perfusion with PGE2 or PGI2 but not
PGF2␣ (1319). However, other investigators reported that
MD-TGF sensitivity was enhanced by tubular perfusion
with PGE2 and PGF2␣, whereas perfusion with PGI2 markedly attenuated feedback sensitivity (1170).
omega hydroxylase (445, 446). It augmented autoregulation of the afferent arteriole in the JMN preparation with
participation of both myogenic and MD-TGF mechanisms
(673, 676) and enhanced the myogenic tone of rabbit and
mouse isolated afferent arterioles (464).
More consistent is the observation that MD-TGF is enhanced by MD generation of prostaglandin endoperoxide
(PGH2) and TxA2 (137, 1589, 1593) or by isoprostanes, all
of which activate TP receptors that can constrict afferent
arterioles and also can enhance Cl⫺ reabsorption from the
TAL of Henle’s loop (38, 437, 932, 1319, 1581, 1591).
Thus activation of TP receptors may augment MD-TGF by
enhancing both the MD signal generated by NaCl reabsorption and the afferent arteriolar responsiveness. TxA2 in gracilis muscle arteries also increased myogenic tone (1502),
which was ascribed to enhanced Ca2⫹ sensitivity of the
contractile apparatus.
Increased transmural pressure in cerebral arteries increased
20-HETE production that activated L-type VOCC currents, myogenic vasoconstriction, and autoregulation of
blood flow (468, 1181). 20-HETE also augmented the myogenic responses of cerebral, skeletal muscle, and mesenteric
arterioles (243, 468). These vasoconstrictor actions of 20HETE were ascribed to blockade of BKca channels on
VSMCs which caused depolarization and activation of
Ca2⫹ entry via VOCCs (677, 943, 1666). 20-HETE also has
been implicated in RBF autoregulation in vivo in some
(1668) but not all studies (1199). It enhanced MD-TGF
activity independent of NKCC2-mediated MD reabsorption, presumably by magnifying the vasoconstrictor response to MD-derived adenosine and/or ATP (464, 1668).
In contrast, vasodilator EETs generated by arachidonate
cytochrome P-450 epoxygenase in endothelial cells in the
JMN preparation blunted the afferent arteriolar autoregulatory vasoconstriction (673). It is not yet clear how cytochrome P-450 enzymes are modulated by RPP is not yet
clear.
Sex differences have been noted in the control of blood
perfusion within the kidney by COX metabolites (1152,
1412). Blood flow autoregulation in cortical and outer medullary regions of kidneys of male rats was efficient and
independent of PGs, whereas poor medullary autoregulation in female rats was attributed to overproduction of PGs.
COX-2 generated vasodilatory metabolites in the JMN
preparation during increased activation of MD-TGF, which
counteracted MD-TGF-mediated constriction of the afferent arteriole and blunted its constrictor response to increased RPP (657, 658). In contrast, COX-1 knockout mice
have a normal MD-TGF response (39). These actions of
COX-2 metabolites were attributed to activation of MD
(39, 232, 577, 657). Thus the rather inconsistent effects of
COX inhibition on renal autoregulation in health may relate to offsetting effects of MD release of vasodilator and
vasoconstrictor prostanoids, confounding effects of sex
differences between COX-1 and-2, and moderating effects
of NO.
Products of COX-2 and nNOS produced in MD cells of the
rat JMN preparation attenuated autoregulation (657, 658).
Inhibition of nNOS no longer enhanced MD-TGF after
blockade of COX-2. Therefore, COX-2 products appear to
blunt autoregulation secondary to MD nNOS generation of
NO. COX inhibition did not affect the myogenic response
of the rat HNK lacking MD-TGF (588), consistent with a
primary effect of vasodilator PGs on MD signaling.
Global inhibition of cytochrome P-450 production of 20HETE and EETs in the JMN preparation (469) or the dog
arcuate artery (777) attenuated the myogenic response. In
contrast, myogenic responses were not affected by global
inhibition of COX-1 and -2 activity. 20-HETE was generated during increased PP in the preglomerular vasculature
and the gracilis muscle arteries by a cytochrome P-450
446
In summary, arachidonate metabolites have complex effects
on both myogenic and MD-TGF mechanisms. PGs generally are not required for overall renal autoregulation. However, MD-TGF response can be enhanced by vasoconstrictor prostanoids and TxA2 and vasoconstriction can be
blunted by vasodilator PGs. In most studies, myogenic responses are increased by 20-HETE and reduced by EETs.
C. NO
Endogenous NO has complex effects on renal autoregulation. It can blunt both myogenic and MD-TGF mechanisms. Whereas NO contributes importantly to the regulation of RVR in many preparations, it does not affect the
overall efficiency of steady-state whole kidney RBF autoregulation over a defined range of RPP. Short-term inhibition
of NOS or administration of an NO donor does not perturb
steady-state RBF autoregulation in the normotensive rat,
the SHR, or the dog (69, 81, 815, 853, 952, 953, 960, 963,
1052, 1109, 1492) nor does it perturb renal cortical or
medullary blood flow autoregulation in the dog (960). NOS
inhibition improved the poor papillary autoregulation
without affecting efficient RBF autoregulation in one study
of the hydropenic Munich-Wistar rat (1127).
Although not affecting steady-state RBF autoregulation in
the plateau phase, NO modulated the range of RPP over
which RBF was autoregulated by shifting the inflection
point to a lower RPP in some (831, 832, 1203), but not all
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CARLSTRÖM ET AL.
studies (69, 81, 815, 853, 952, 953, 960, 963, 1109, 1492,
1494).
On the other hand, increased NO release in the JMN preparation attenuated PP-induced diameter adjustments of the
cortical radial artery and afferent arterioles (675, 1184) by
reducing myogenic and MD-TGF responses. Inhibition of
NOS improved the myogenic response of afferent arterioles
of JMN preparation perfused with a cell-free artificial solution (675, 1184). Autoregulation of this preparation was
improved with the use of erythrocytes or albumin in the
perfusate that scavenge NO (192, 1168, 1184). Thus endogenous generation of NO can blunt both the MD-TGF
and myogenic mechanisms and yet has little effect on
steady-state autoregulation of RBF.
Moreover, global inhibition of NOS, or selective blockade
of nNOS, magnifies MD-TGF responses in superficial
nephrons whether assessed by micropuncture and microperfusion (38, 116, 133, 188, 661, 761, 1052, 1228,
1463, 1493, 1515, 1553, 1586, 1587, 1602, 1608, 1609) or
by wavelet analysis of blood flow oscillations of superficial
nephrons (1402). Oscillations in RBF and RVR often become readily apparent after NOS inhibition. Comparison
of oscillations in blood flow in the efferent arteriole and the
whole kidney led to the conclusion that NO attenuates
the strength of arteriolar oscillations mediated by both the
myogenic and the MD-TGF mechanisms while improving
their synchronization (1402).
Dynamic studies have demonstrated that NO slows and/or
attenuates renal myogenic vasoconstriction. Inhibition of
NOS in the rat augments the strength and speed of the
myogenic response to a rapid, step increase in RPP (FIGURE
7A). This increased the contribution of the myogenic mechanism from 35 to 80% (299, 750) or 45 to 100% (1626). As
is shown in FIGURE 7A, NOS inhibition also shortens the
time to completion of a myogenic response from ⬃8 to 4 s.
Indeed, inhibition of NOS augmented the myogenic response sufficiently to induce complete autoregulation
thereby providing transmission of little error signal to MD
cells to activate MD-TGF.
Vascular admittance transfer function analysis in conscious
dogs (754) or in some (750, 1357, 1358, 1402, 1573), but
not all (1340), conscious or anesthetized rats confirmed that
endogenous NO can attenuate the strength of the renal
myogenic response. NOS inhibition primarily enhanced the
myogenic mechanism by increasing the slope of reduction in
admittance gain between 0.05– 0.20 Hz (FIGURE 7B) and
the height of the associated phase peak in normotensive
(Long-Evans, SD, and Wistar) rats but not in SHR (1341,
1358, 1563, 1569), which could possibly be explained by
reduced NO signaling or bioavailability in their kidney due
to excessive ROS. The slope of the decline in admittance
gain increased from ⬃30 to ⬃55 dB/decade, suggesting the
emergence of a second-order component responding to the
rate of change in BP in addition to the actual level of BP.
NOS inhibition increased the fractional compensation from
40 to 58%, which indicates an enhanced vigor of the myogenic response. However, in this study, the corner frequency where admittance began to decline was largely unaffected by NOS inhibition, which indicates a maintained
rate of myogenic contraction. Moreover, the markedly attenuated myogenic response in normotensive BN rat with
forced increases in RPP (1563) was normalized by inhibition of NOS (1563, 1569, 1570) (see sect. VIIB8).
There is controversy about the origin of the NO that modulates the renal myogenic response. Early studies of rabbit
isolated perfused afferent arterioles or afferent arterioles of
the rat HNK indicated that the NO that attenuated the
myogenic responses was generated by the endothelium
(586, 593, 696, 702, 747). Moreover, stimulation of endothelial-derived NO by activation of vascular ETB receptors
blunted the myogenic response of the rat isolated renal and
mesenteric arteries (1096) and the whole kidney (1357). In
contrast, a unique renal source was implicated by the finding that NO modulated the myogenic response in the rat
kidney but not in the hindlimb (750). This was ascribed to
blunting of myogenic tone by nNOS-derived NO in the MD
rather than by NO produced by the vascular endothelium
(FIGURE 7). However, NOS inhibition in some other studies
of nonrenal vessels, such as skeletal muscle arteries, mesenteric arteries, and splenic arterioles, accelerated or magnified myogenic constriction, thereby implicating eNOS in
these extrarenal vascular beds (154, 377, 519, 944, 1339,
1530).
Selective inhibition of nNOS in the JMN preparation enhanced the autoregulatory constrictor responses to increased PP of the afferent arteriole (FIGURE 7D) (657, 658,
662). The NO signal arose from MD cells since the effect of
nNOS inhibition was abolished by elimination of MD-TGF
by papillectomy. However, it is not clear from these JMN
studies whether NO affects primarily the myogenic or the
MD-TGF mechanism. Support for the view that MD-derived NO attenuates myogenic tone derives from the finding
that NOS inhibition did not enhance myogenic constriction
in preparations lacking functional MD cells, i.e., mouse
isolated perfused afferent arterioles with endothelium present (866) or rat afferent arterioles in the HNK preparation
(FIGURE 7C) (1358). Moreover, isolated perfused afferent
arterioles from eNOS-deficient mice retained normal myogenic response (866). In addition, NOS inhibition did not
affect afferent arteriolar constrictor responses in the artificial fluid-perfused JMN preparation to increased RPP
(675). These studies appear to exclude a major role for NO
derived from eNOS in afferent arterioles and implicate
nNOS-derived NO in the MD as the primary source that
attenuates the strength of the myogenic response in intact
kidneys.
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RENAL AUTOREGULATORY MECHANISMS
Collectively, there are several lines of evidence to support
the notion that NO generated by MD cells attenuates myogenic response of the preglomerular vasculature by buffering the speed and/or the strength of the myogenic mechanism (750, 1358, 1569). Support derives from studies of
renal vascular dynamics based on responses to a rapid, step
increase in RPP, on frequency analysis of transfer function
admittance gain and a dependence on MD-TGF activity. In
some studies, the myogenic response after acute global NOS
inhibition became so rapid and robust that the autoregulatory response to a step increase in RPP was complete within
10 s without any evidence of participation of a MD-TGF or
other mechanisms. The exaggerated myogenic system during NOS inhibition appeared to have become sufficiently
potent to prevent an error signal from reaching the MD to
activate MD-TGF and other mechanisms. Global NOS inhibition may prevent modulation of myogenic responses by
NO generated from any source. However, the enhancing
effect of L-NAME on the myogenic response was linked to
MD nNOS since it was reduced (1358) or abolished (750)
by furosemide.
Frequency analysis reported that global inhibition of NOS
in Long-Evans, SD, and Wistar rats (FIGURE 7B) (1569) or
selective intrarenal inhibition of nNOS, but not iNOS, augmented the myogenic contribution to dynamic autoregulation in SD rats (1358). Selective inhibition of nNOS in vivo
increased the slope of admittance gain decline from 24 to 42
dB/decade, a change similar to that observed with global
NOS inhibition with L-NAME (1358). These results indicate that MD-derived NO is an important pool to attenuate
the myogenic responses of the preglomerular vasculature in
the kidney.
A recent study questioned this view. Pharmacological inhibition of NOS, but not nNOS or iNOS, increased the speed
and strength of the myogenic response to a step increase in
RPP without perturbing overall steady-state RBF autoregulation in rats (299). In agreement, global NOS inhibition
magnified the myogenic component of RBF autoregulation
in wild-type mice and nNOS mutants, but not in mice lacking eNOS (299). This suggests an NO-independent role for
eNOS that warrants further investigation.
The cellular events by which NO attenuates VSMC myogenic responses are incompletely understood. In one study
of the renal microcirculation, exogenous NO signaled via
cGMP-dependent and -independent pathways depending
on its concentration (1486). Low renal NO concentrations
(⬍1 ␮M) that appear to be in the physiological range signal
primarily through cGMP (887, 1486). Kurtz and colleagues
(1283) demonstrated that NO generated cGMP that caused
renal vasodilation primarily by inhibiting phosphodiesterase 3 that degrades cAMP. NO donors, and high levels of
8-bromo-cGMP, completely abolished autoregulation of
preglomerular vessels in the JMN preparation (132), indi-
448
cating inhibition of both myogenic and MD-TGF mechanisms. Since stimulation of cGMP by atrial natriuretic peptide (306, 904, 1644) failed to restore RBF or reverse the
exaggerated myogenic response detected by transfer function analysis following NOS inhibition (1573), there must
be different pools of renal NO that regulate vascular responses.
There are multiple sites where NO, cGMP, or its target
PKG and cAMP/PKA could dampen Ca2⫹ signaling or sensitivity, and thereby moderate arteriolar tone (434). NO in
the renal vasculature reduced agonist- or stretch-induced
increases in Ca2⫹ influx by inhibiting VOCCs or TRPC
channels or by activating BKCa channels (403, 408, 832,
898, 1011, 1642, 1645). NO in the afferent arteriole is
reported to inhibit both L- and T-type VOCCS (408), which
could account for its ability to antagonize both MD-TGF
and myogenic responses. Moreover, NO in VSMCs suppressed ADP-ribosyl cyclase activity, thereby reducing
RyR-mediated Ca2⫹ mobilization (403, 898, 1642). Both
NO and ROS in VSMCs regulated RyR-mediated Ca2⫹
mobilization (384, 1645), but by distinct signaling pathways (752, 861, 866, 1224). NO dilated gracilis muscle
arteries and afferent arterioles by activating MLCP (129,
1499, 1503), and attenuated myogenic tone of nonrenal
vessels by inhibiting Rho kinase in VSMCs (475, 1214,
1458). This may also occur in the renal microcirculation
(1358). NO inhibition of 20-HETE formation or action
diminished myogenic constriction of coronary arteries (21,
645, 921, 1144). Thus NO has multiple mechanisms that
can reduce vascular tone and/or Ca2⫹ sensitivity.
NO also could impact the myogenic response indirectly by
attenuating MD-TGF signaling. NO from nNOS can inhibit reabsorption of NaCl by activated MD cells, thereby
blunting the signal for MD-TGF responses (702, 1460,
1602). NO and GMP signaling in the MD phosphorylates
and inhibits NKCC2 and thereby reduces luminal NaCl
uptake (828, 1228). Moreover, NO inhibited ecto-5’-nucleotidase that is the final enzyme in the conversion of ATP to
adenosine, which can limit MD-TGF activation (1287). NO
and O2⫺ interact in MD cells where O2⫺ inactivates NO and
enhances MD-TGF responses during oxidative stress (913,
1393). The effect of NOS inhibition to enhance the renal
myogenic response can be dissociated from renal or systemic vasoconstriction in most (750, 754, 1358, 1573) but
not all studies (1572). The enhancement of myogenic responses by NOS inhibition in vivo can be prevented by
furosemide, thereby implicating MD-TGF (755, 1193,
1563).
In summary, NO has complex interactive effects on renal
autoregulation. It modulates both the dynamics and the
steady-state contribution of individual mechanisms. There
are mixed results for a role of NO derived from the endothelium of the afferent arteriole in blunting the myogenic
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response. More convincing evidence demonstrates that NO
generated by nNOS in the MD not only attenuates MDTGF but also restricts the speed and strength of the myogenic response. During NOS inhibition, the myogenic tone
can become sufficiently strong to account for nearly all of
the highly efficient renal autoregulation (FIGURE 7, A AND
B). The possible role of NO in vasomotion of isolated arteries/arterioles was discussed in section IIE.
D. Carbon Monoxide
Constitutively active heme oxygenase 2 (HO-2) and inducible HO-1 catalayze heme to CO, iron, and bilverdin.
HO-2, but not HO-1, is highly expressed in endothelial and
VSMC. CO produced a biphasic response in the renal vasculature, with vasodilation at low concentrations (100 nM)
and vasoconstriction at high concentrations (1–10 ␮M)
(1445). These vasoactive effects were ascribed to stimulation of NO production by endothelial cells and inhibition of
eNOS, respectively. CO attenuated the actions of vasoconstrictors in isolated interlobar arteries by activating VSMC
K⫹ channels (1653).
Induction of HO-1 in rat kidneys increased basal RBF but
did not impair the efficiency of RBF autoregulation (130).
However, induction of HO-1 in tubular epithelial cells in
the rat JMN preparation increased CO production that
blunted the myogenic tone of afferent arterioles, whereas
biliverdin was without effect (131). The reason for discrepancy between whole kidney autoregulation in vivo and that
recorded for myogenic responses of the afferent arteriole of
JMN in vitro requires further investigation.
The MD expressed HO-1 and HO-2 that generated CO and
inhibited MD-TGF in vivo via activation of sGC and cGMP
signaling (1557). Biliverdin appeared to attenuate MDTGF activity by scavenging O2⫺ (1557). Both CO and biliverdin inhibited MD-TGF in the rabbit isolated JGA preparation (FIGURE 6) (1222, 1225, 1226).
The HO inhibitor chromium mesoporphyrin decreased renal HO-1 and CO but did not affect RBF or GFR or NO
production in the rat (718). In another study, HO inhibition
increased RVR in the rat kidney which was more pronounced when NOS was inhibited (1242). On the other
hand, HO and CO in the renal medulla may participate in
the regulation of medullary blood flow, Na⫹ excretion, and
BP (897, 1665). CO blunted rat gracilis arteriolar myogenic
responses (830) and attenuated VSMC myogenic tone by
activating BKCa channels to increase EM (881, 1653).
In summary, CO at low concentrations in vitro in isolated
preparations generates NO that activates sGC signaling to
produce vasodilation and inhibit both the myogenic and
MD-TGF mechanisms. However, CO has little effect on
RBF autoregulation in vivo. Renal HO-1 is often induced
during pathophysiological conditions (6, 1062), which
might be a pathway to attenuate autoregulation and accelerate barotrauma. Thus, despite this potential, the roles or
the underlying mechanisms of CO and HO in autoregulation are not clearly established.
E. Endothelin-1
Endothelin is produced primarily by vascular endothelial
cells and by tubular cells of the TAL of Henle’s loop and the
CD. Renal vascular actions of endothelin (ET)-1 are mediated by vasoconstrictor ETA and ETB receptors on VSMCs
and vasodilator ETB receptors on vascular endothelial cells
linked to NO production. Steady-state RBF autoregulation
was unaffected by ETA receptor blockade (97, 140) or by
combined blockade of ETA⫹ETB receptors (831). However, blockade of ETB, but not ETA, receptors enhanced the
myogenic response in vivo and intrarenal arteries in vitro by
inhibiting NO production (453, 1357). For actions of NO
on RBF autoregulation and individual components, see section VIIC. A low concentration of ET-1 that does not contract afferent arterioles in the HNK potentiated myogenic
reactivity by increasing PKC and its modulation of K⫹
channels (802). Mechanistically, Kirton and Loutzenhiser
(802) proposed activation of PKC and modulation of K⫹
channel activity, but as discussed in next section ET-1 may
also activate NADPH oxidases.
F. Reactive Oxygen Species
Reactive oxygen species (ROS), such as O2⫺, H2O2, and
hydroxyl anion (OH.⫺), are reactive byproducts of mitochondrial respiration, uncoupled NOS, or specific oxidases,
notably NADPH oxidase, xanthine oxidoreductase, and
certain arachidonic acid oxygenases. NADPH oxidase is a
major source of renal and vascular ROS (494, 895, 1016,
1086, 1151). It is a multiunit enzyme comprising the membrane-bound neutrophil oxidase (NOX) unit, either
NOX-1, NOX-2 (gp91phox), NOX-4, or NOX-5. All vascular NOXs generate ROS, but their intracellular distribution, their requirement for interaction with the NOX subunits p22phox, p47phox (or NOXO1), p67phox (or NOXA1),
and p40phox and the small G protein Rac-1 or Rac-2, and
their modes of regulation and generated ROS (O2⫺ or H2O2)
differ (78, 136, 1086). For activation of the enzyme, participation of Rac 2 (or Rac 1) and Rap 1A (128), but also PKC
are considered crucial (136).
The kidney has a rich, diverse, and cell-type specific distribution of NADPH oxidases (471). ROS were produced in
all renal vascular and tubular cells studied (40). NOX-1
was expressed primarily in large vessels, whereas NOX-2
and NOX-4 were expressed abundantly together with their
chaperone protein (p22phox) in resistance arterioles.
NOX-5 was expressed in human, but not rodent, vessels
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RENAL AUTOREGULATORY MECHANISMS
(78, 182, 873, 1150, 1477). The afferent arteriole and MD
cells both expressed NOX-2 and NOX-4 and the subunits
capable of generating O2⫺ or H2O2 (471, 1603, 1657). The
rat and rabbit afferent arteriole expressed p22phox that was
required for activation of NOX-1, NOX-2, and NOX-4
(471). NADPH oxidase-mediated O2⫺ generation in MD
cells enhanced MD-TGF in large part by limiting NO bioavailability (912, 913, 1608). Flow-dependent NaCl reabsorption, or stimulation by ANG II, primarily activated MD
NOX-2 and enhanced MD-TGF signaling, whereas NOX-4
contributed to basal ROS production (448, 912).
Oxidative stress implies an increased production, or a
decreased scavenging or metabolism of ROS. Many effects of oxidative stress can be attributed to NO deficiency. Increased NADPH oxidase-derived O2⫺ production and vascular dysfunction have been reported in hypertension, diabetes, atherosclerosis, and CKD (40, 895,
1604). This section primarily focuses on the roles of vascular O2⫺ and H2O2 in renal autoregulation in health,
whereas section VII considers the pathophysiological
contribution of ROS.
Preliminary studies suggested that renal autoregulation in
vivo to a step increase in RPP was dependent on NADPH
oxidase whose inhibition with apocynin attenuated myogenic response, but had little effect on MD-TGF and the
third mechanism. The enhanced myogenic response following inhibition of NOS was largely prevented by inhibition
of NADPH oxidase or by tempol (752). Thus the enhancement of myogenic responses by NADPH oxidase-derived
O2⫺ was offset by interactions with NO and by metabolism
of O2⫺ by superoxide dismutase (SOD). Indeed, many studies in the renal vasculature have concluded that ROS can
regulate vasomotor tone by direct effects on VSMC and by
quenching and inactivating NO (758, 1301, 1603, 1604).
O2⫺ in the JGA enhanced vasoconstriction by scavenging
and inactivating NO (1217, 1301, 1588, 1592, 1603,
1608), but also acted directly on the afferent arteriole. The
inhibition of MD-TGF by tempol was enhanced by endothelium removal (913), suggesting a primary action of ROS
and modulatory role for NO.
Activation of GPCRs in VSMCs rapidly increased O2⫺
that potentiated Ca2⫹ signaling in afferent arterioles and
renal vasoconstriction (183, 399, 400, 864). Thus renal
vasoconstriction with ANG II, ET-1, NE, or U-46619
was blunted by inhibition of NADPH oxidase, genetic
deletion of p47phox or NOX-2, or by metabolism of ROS
by SOD or tempol (182, 183, 758, 759, 864, 1037,
1301). O2⫺ generated by NADPH oxidase in afferent arteriolar VSMC activated ADP-ribosyl cyclase to increase
Ca2⫹ mobilization by RyRs (399, 400, 1456), whereas
NO suppressed ADP-ribosyl cyclase activity to reduce
[Ca2⫹]i (403, 898, 1642).
450
The enhancement of myogenic responses by ROS may
involve activation of GPCR coupled to second messengers, cytosolic proteins, and [Ca2⫹]i (FIGURE 8) (1328)
linked to redox signaling by vascular NADPH oxidases
(1086). Moreover, stretch activation of AT1 receptors, in
the absence of ANG II, enhanced the myogenic tone of
cerebral and renal cortical radial arteries via ROS generation (999).
Several studies have demonstrated potentiation of renal vasoconstriction by ROS generation. Thus contraction of rabbit isolated afferent arterioles to U-46619 was enhanced by
vascular ROS and blunted by NO (1301, 1303). The sensitivity of afferent arterioles to ANG II was enhanced markedly in mice with SOD1 (Cu-Zn-SOD) deficiency (183).
This effect was primarily attributed to enhanced O2⫺ inactivation of NO. Conversely, prevention of NADPH oxidase-derived O2.⫺ generation in afferent arterioles from
p47phox knockout mice blunted ANG II and myogenic contractions (183, 864, 1097), whereas myogenic contractions
were preserved in afferent arterioles from eNOS-deficient
mice (864). Thus O2⫺ generated by ANG II enhances afferent arteriolar contractions by inactivation of NO, whereas
O2.⫺ generated by increased PP enhances myogenic contractions independently of NO. PP increased the generation
of O2⫺ from NADPH oxidase in large conduit vessels (1621)
and in afferent arterioles from rats (1224) or mice (702,
861, 866, 1224). Cell-permeable polyethylene glycol
(PEG)-SOD and tempol both blunted the myogenic responses of mouse isolated afferent arterioles, whereas PEGcatalase was ineffective, thereby implicating O2⫺ rather than
H2O2 (866). Tempol also attenuated myogenic responses in
the rat isolated perfused HNK (1146). Moreover, prolonged infusion of ANG II increased ROS production that
enhanced myogenic response of isolated afferent arteriole
(864).
Taken together, many studies have implicated O2⫺ generated by NADPH oxidase/p22phox/p47phox NOX-2 during
stretch of afferent arterioles in potentiating the myogenic
response. However, there are contrary findings. For example, the myogenic response of isolated afferent arterioles of
normotensive WKY rats did not require ROS generation,
although O2⫺ enhanced the myogenic response of SHR afferent arterioles (1224). Transforming growth factor-␤1
(TGF-␤1) perfused into the JMN preparation antagonized
myogenic constriction by generation of ROS from NADPH
oxidase (1354). However, this growth factor caused prominent basal constriction of the afferent arteriole, which may
have obscured an additional myogenic contractile response.
Moreover, TGF-␤1 activity and its ability to increase BP
and myogenic tone of mesenteric arteries were normally
suppressed by Emilin-1, a protein of elastic extracellular
matrix (196). Intrarenal infusion of hypoxanthine plus xanthine oxidase increased O2⫺ and caused vasoconstriction as
well as natriuresis, but steady-state RBF autoregulation was
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well maintained (1204). A high-salt diet that activated NADPH oxidase and increased ROS production in kidneys
(471, 579) failed to affect the myogenic transfer function in
rats and, when given with ANG II, actually blunted the
myogenic response (1273). Another study of rats fed 8%
NaCl for 2 wk reported that RBF autoregulation was abolished (AI increased from 0.0 to 1.4) and the autoregulation
of afferent arterioles of JMN was blunted by an apparent
increase in ROS which was restored in part by prolonged
treatment with apocynin (396). The reason for these discrepancies is presently unclear but may relate to different
effects of O2⫺ and H2O2.
Increased ROS formation enhanced myogenic responses in
other vascular beds including mesenteric resistance arteries
(1530) and tail arterioles (1097). Elevated PP in gracilis
muscle arteries activated sphingosine kinase-1 to stimulate
production of ROS from NADPH oxidase that enhanced
Ca2⫹ sensitivity and myogenic responses likely by activation of Rac and RhoA/Rho kinase and inhibition of MLCP
(783). Activation of NADPH oxidases by increased PP in
bovine coronary and rat small cerebral arteries enhanced
myogenic contractions and/or autoregulation of blood flow
by activation of the ERK/MAPK cascade (1104), or by activating PI3K/Akt signaling that reduced BKCa activity, and
increased EM and VSMC [Ca2⫹]i (468, 470, 1454). However, low levels of O2⫺ generated by subdural perfusion of
xanthine plus xanthine oxidase decreased cerebral blood
flow, but did not affect autoregulation (1646), whereas high
levels of ROS increased blood flow and inhibited blood flow
autoregulation and myogenic constriction by activating
BKCa channels that hyperpolarized the VMSC plasma membrane. This suggests an effect of H2O2, which is known to
hyperpolarize VSMCs (1646). ROS-mediated vasodilation
counteracted myogenic tone in rat ophthalmic arteries, but
this effect was partially dependent on intact endothelium,
which is a source of H2O2 as well as NO (1543). Indeed,
ROS, probably H2O2, impaired endothelium-dependent
vasodilation by inhibiting BKCa channels in renal artery
endothelial cells (135). H2O2 can increase endothelial NO
production (721) and decrease Ca2⫹ sensitivity in aortic
VSMCs (663).
In summary, ROS impacts renal autoregulation by modulating both myogenic and MD-TGF mechanisms. Most
studies of isolated afferent arterioles concluded that the
NADPH oxidase/p47phox/NOX-2 signaling pathway is activated by increased RPP and is the major source of O2⫺ that
enhances the myogenic constrictor response, whereas H2O2
may inhibit this response. The opposing effects of these two
ROS may account for some inconsistences in the reported
effects of ROS on autoregulation, but this requires further
study. The mechanisms whereby O2⫺ sensitizes contractions
involve reduced NO bioavailability, but the effects on the
myogenic response likely involve direct VSMC effects to
mobilize [Ca2⫹] or increase Ca2⫹ sensitivity.
G. Endothelium-Derived Hyperpolarizing
Factor and Cxs
Endothelial cells control vascular tone by changes in EM
transmitted to VSMC and by the release of factors that
relax or constrict VSMCs. Endothelial dilator factors include NO, PGs, and EDHF. ACh and bradykinin can elicit
vasodilation and buffer vasoconstriction in part via EDHF
that hyperpolarizes VSMCs and relaxes intrarenal arterioles independent of the vasodilators NO, PGE2, and PGI2.
EDHF stimulated Na⫹-K⫹-ATPase and enhanced hyperpolarization of the renal interlobar artery (172). EDHF in mice
was estimated to contribute ⬍20% of the renal vasodilation
produced by ACh or bradykinin (299).
Little is known about the influence of EDHF on RBF autoregulation. Although the myogenic response is not mediated by endothelial factors, it is likely that endothelial cells
can modulate VSMC tone by electrical coupling and production of paracrine agents such as NO as well as EDHF
and EETs. ACh-induced EDHF production transiently
blunted myogenic vasoconstriction of afferent arterioles in
the isolated perfused rat HNK (592) where it stimulated K⫹
channels to modulate afferent but not efferent arteriolar
tone, presumably by affecting EM and VOCC activity
(1571). Interestingly, the inhibition was transient, reversing
after 5–10 min.
EETs mediated EDHF actions in the rabbit isolated, perfused afferent arteriole. They were generated by a cytochrome P-450 epoxygenase and elicited vasodilation by
opening BKCa channels and activating Na⫹-K⫹-ATPase on
VSMCs (1551). A metabolite of cytochrome P-450 epoxygenase, presumably an EET, blunted myogenic constriction
of afferent arterioles in the JMN preparation (673). Vasodilatory EETs attenuated the myogenic response of isolated
gracilis muscle arterioles (1424). Metabolism of EETs by
soluble epoxide hydrolase regulated myogenic response and
BP via effect on Ca2⫹ entry via TRPC1 and TRPC4 channels (1209). Other candidates for an EDHF include H2O2
and hydrogen sulfide (H2S) (914, 1449, 1652).
Gap junctions composed of Cxs may contribute to endothelium-dependent vasorelaxation via conducted vascular responses. The extent to which cell-to-cell communication
depends on direct signaling through myoendothelial gap
junctions is controversial. Isolated arteries and arterioles
displayed bidirectional electrical coupling between endothelial cells and VSMCs. Vasodilator waves passing via cellto-cell gap junctions can spread to upstream feed arteries
that control blood flow into arteriolar networks (60). Cx
may mediate this spreading vasodilation elicited by EDHF
by transfer of hyperpolarization from endothelium via gap
junction Cx to adjacent VSMCs to conduct along the vessels and thereby close their VOCCs. However, such coupling between endothelium and VSMC cells has not been
verified in intact animals where myoendothelial gap junc-
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RENAL AUTOREGULATORY MECHANISMS
tions may be controlled by yet unknown mechanisms that
impede such signaling (313, 314). In nonrenal vascular beds
including aorta, pulmonary, and coronary arteries, Cx40
and Cx37 interacted to form heterotypic channels, and they
were codependent on each other, or mutually dependent,
for optimal expression and function in vascular endothelium (1368, 1369, 1599, 1633).
ACh acting on cremaster arteries in vitro elicits local vasodilation that was conducted upstream via Cx40, but not on
Cx37 (738). However, vasodilation produced by ACh in
mouse cremaster arterioles in vivo was largely independent
of this mechanism (125, 314, 315, 1362). Moreover, ACh
produced potent vasodilation in Cx40-deficient gracilis arteries in vitro or in endothelium-specific Cx40 deficient vessels, but this was detected only under isobaric conditions
(125). ACh-induced EDHF-like dilation observed in vivo
was independent of the presence of Cx40 (756). Thus ACh
responses appear to be conducted along VSMCs, but not
between endothelial cells.
Cxs at myoendothelial gap junctions of small arteries in
vitro modulated the effects of NO on Ca2⫹ signal propagation which prolonged increases in [Ca2⫹]i in endothelial
cells and accelerated Ca2⫹ signal transmission in VSMCs
(1192), but this was independent of Cx37 (419).
In summary, the roles of Cxs in the EDHF response and in
myogenic tone are unclear. The role of gap junctions and
Cx in the conduction of vasoactive signals along the vascular tree of the microcirculation requires further investigation and resolution concerning differences in results obtained in vitro and in vivo.
H. Modulation of Myogenic Responses by
Agents Released From Activated MD or
CT Cells
Both MD, and some CT, cells abut the afferent arteriole
supplying the parent glomerulus. As discussed earlier in
section IIA3, MD cell signaling is activated by reabsorption
via luminal NKCC2 and Na⫹/H⫹ exchange. As summarized in FIGURE 6, MD-derived metabolites can either enhance (ATP, adenosine, PGH2, TxA2, and O2⫺) or inhibit
(NO, CO, and PGE2) afferent arteriolar tone. As discussed
in section IIB2, CT cell signaling can be activated by reabsorption via luminal ENaC which release EETs and PGE2
that attenuate afferent arteriolar tone (FIGURE 6). The resultant vasodilation from CT-GF activation may contribute
to resetting of MD-TGF during salt loading (1554). Such
rich paracrine signaling in the JGA provides for complex
interactions between the tubular-glomerular systems and
myogenic mechanism of vascular control and contributes to
the positive and negative interactions that were described in
earlier sections.
452
VII. RENAL AUTOREGULATION IN
DISEASE: HYPERTENSION, RENAL
DISEASE, AND DIABETES
A. Introduction
Studies in the 1930s demonstrated that hypertension is associated with arteriolosclerosis of the small renal arterioles
and renal tubulointerstitial inflammation, fibrosis, and glomerulosclerosis (795, 1033). There were two contrasting
theories concerning the principal causes and the secondary
compensations (388, 1033, 1541). One held that hypertension is primary and induces secondary renal and vascular
abnormalities. In 1937, Moritz and Old (1033) reported
that renal afferent arteriopathy was present in 98% of autopsied kidneys from subjects who had hypertension but in
only 15% of these who were normotensive. They concluded
that the renal arterial lesions are a consequence of the hypertension. The earliest structural changes with hypertension are in the smallest resistance arterioles, a site where a
myogenic response plays a fundamental role. Hypertension
is associated with structural remodeling of the vascular wall
and vascular hyalinization, but the contribution of wall
remodeling to functional changes in myogenic responses is
uncertain. The second theory held that renal inflammation
and afferent arteriopathy are primary and induce hypertension (1033). In 1934, Goldblatt (476) showed convincingly
that creating a renal artery stenosis to reduce the RPP leads
to hypertension. Renal artery stenosis, whether caused by
atherosclerosis or fibromuscular disease, is detected in
5–10% of patients with hypertension (1455). However, recent controlled clinical trials of renal artery angioplasty and
stenting to correct a stenosis have concluded that hypertension, although often lessened in severity, is only rarely cured
(72). Thus the debate remains incompletely resolved. Structural renal arterial lesions that limit RPP clearly raise BP.
However, the renal arteriolar remodeling that accompanies
sustained hypertension likely impairs regulation of RBF and
RPP and increases RVR and may thereby contribute to
sustaining the hypertension. Thus the structural renal arterial changes can be viewed as a consequence of hypertension, but in some settings, likely also contribute to the development or severity of the hypertension. Therefore, they
are of considerable importance.
Glomerular hyperfiltration refers to an increase in the
SNGFR, but this is not necessarily accompanied by glomerular hypertension, i.e., an increase in the PGC (601). Schmieder and co-workers (1297, 1298) suggested that glomerular
hyperfiltration occurs early in hypertensive patients with
target-organ damage, and Campese et al. (177) concluded
that PGC is likely increased in a group of salt-sensitive hypertensive patients that included many African-Americans.
An impaired renal autoregulatory response in hypertensive
African-Americans (FIGURE 2A) may contribute to an increased PGC (826).
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Many rodent hypertensive models eventually develop CKD
(104). However, the development of CKD, unless associated with malignant hypertension, is uncommon in humans
except in African-Americans. Recent studies report that the
primary problem in African-Americans with CKD is inheritance of an abnormal genotype that confers increased risk
of renal damage. Hypertension is usually a secondary consequence (909). Nevertheless, it is clear that once renal
damage has been sustained, hypertension is one factor predicting the rate of further decline in renal function, especially in those with heavy proteinuria (803).
Autoregulation normally protects the glomerular and tubulointerstitial tissues from hypertensive injury (108, 112,
933). However, although autoregulation usually adapts to
higher BPs in hypertensive models, its efficiency often declines over time. The responsible mechanisms are poorly
understood. Some, but not all, models of hypertension,
CKD, or diabetes mellitus (DM) have impaired renal autoregulation that permits transmission of more of the BP fluctuations to the glomeruli where it increases the PGC. The
degree of glomerular injury in hypertensive models generally increases in proportion to the impairment in renal autoregulation (106, 107, 110). Bidani, Kriz, Byrom, and colleagues (103–110, 173, 839, 840, 1162) proposed that hypertension combined with impaired renal autoregulation
cause renal barotrauma and enhance the progression of
CKD. Kriz et al. (838) demonstrated that an initial podocyte injury from barotrauma in the context of FSGS misdirects filtration into the interstitium, thereby initiating a
spreading renal tubulointerstitial inflammation and later
fibrosis with degeneration or fibrosis of the glomerulus and
its attached tubule.
It follows that the ideal therapy for hypertension should
lower the BP while preserving, or improving, the effectiveness of the renal autoregulation (105, 106, 110, 500). Ideally, the preglomerular vasculature should protect the kidney from both sustained hypertension and from rapid oscillatory fluctuations in BP (108, 109, 927, 934) since both
increased BP and increased pulse pressure predict hypertensive renal damage (108, 927, 933).
Examples of impaired autoregulation in disease models include rodent remnant kidney models of CKD with prolonged RRM, some, but not all, rodent insulinopenic or
obesity-associated models of DM, or Dahl salt-sensitive or
Goldblatt ischemic renovascular hypertensive models. In
contrast, SHR retain highly efficient autoregulation
throughout life that likely contributes to their resistance to
proteinuria and glomerulosclerosis even with established
and prolonged hypertension. Renal cross-transplantation
between BN rats and SHR proved that the protection from
glomerular damage in the SHR was intrinsic to their kidneys (260), which corresponds to the excellent autoregulatory adjustments of the preglomerular vasculature of the
SHR but the much weaker adjustments of BN rats. A similar kidney cross-transplantation study demonstrated that
the kidneys from stroke-prone SHR (SHR-SP) exhibit more
hypertensive damage and malignant nephrosclerosis than
those of SHR during a high-salt diet (261, 498). Moreover,
poor RBF autoregulation in Fawn-Hooded (FH) rats is improved by replacing chromosome 1 genetic loci from BN
rats (922, 1610). Roman, Provoost, and colleagues have
provided extensive information concerning the mechanisms, and their genetic components, that underlie autoregulation in many hypertensive models, as described in detail
under the individual models below. These studies are important because they have established that the efficiency of
renal autoregulation and the associated protection of the
kidneys from hypertensive damage are heritable.
B. Hypertension
1. SHR
SHR are considered a model of human essential hypertension (1115, 1483). The strain was developed from inbreeding of selected rats that developed hypertension spontaneously. Hypertension develops progressively over 4 – 8 wk
while fed a normal-salt diet (161, 386, 744, 867, 1009,
1389, 1467). The hypertension is exacerbated by a high salt
intake (34, 256, 325, 326, 447, 498, 880, 917, 978, 1406).
The degree of elevation in BP was quite variable among
studies. Factors likely contributing to this variability are the
methodology for BP measurement, the animals initial age
(6 –14 wk), duration of treatment (2–28 wk), the amount of
salt in the diet (ranging from 1 to 8%), as well as the genetic
background of the SHR and control WKY colonies (848,
849, 1428). Cross-transplantation of kidneys between SHR
and normotensive controls established that the kidney of
SHR is the primary cause of the development of hypertension (506, 575, 779, 1158, 1235, 1236).
Renal hemodynamic abnormalities are important in the initiation of hypertension in the SHR. Basal GFR and RBF are
reduced during the development of hypertension in young
SHR (4 –10 wk old) (335, 386, 567, 574, 1038, 1252, 1507,
1526), but are restored to the levels of normotensive WKY
rats during the established phase at 12–20 wk (42, 418,
443, 574, 809, 1246, 1252). A rightward shift in the pressure-natriuresis curve to a higher level of RPP (43, 443, 997,
1093, 1246) led to an early period of relative Na⫹ retention
during the development of hypertension (79, 570, 571, 605,
940). A genetic link between abnormal renal hemodynamics and the development of hypertension was established in
cross-breeding studies between SHR and WKY. Renal vasoconstriction (reduced RBF and GFR) and elevated BP
cosegregated (572, 710) and was evident during the early
development phase of hypertension, suggesting causality.
This link has been investigated extensively. Cosegregation
of the renin allele of SHR with increased BP has been noted
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RENAL AUTOREGULATORY MECHANISMS
(850, 1427, 1641), and expression of the SA region on
chromosome 1 is enhanced in hypertensive SHR (693, 711,
712, 906, 1405), in particular in the proximal tubule
(1631). However, studies using congenic SHR carrying a
smaller segment of BN chromosome 1 but without the SA
gene concluded that molecular variation in this gene was
not required for the effect of this region of chromosome 1
on blood pressure (1405).
The RAS is especially important in the developmental phase
of hypertension. ACE inhibition in young SHR for 4 wk
between 2 and 10 wk of age normalized the exaggerated
renal vasoconstriction and has long lasting effects in preventing full expression of hypertension later in life (250,
354, 417, 472, 567, 568, 573, 574, 939), beneficial effects
independent of changes in renal vasculature structure (786).
Administration of an AT1 receptor blocker from 3 to 8 wk
of age led to a sustained reduction in BP in adult SHR (95,
1103). Although less well studied, blockade of the RAS may
be efficacious in reversing established hypertension (355,
393, 939).
Renal nerves have an important role in the pathogenesis of
hypertension in the SHR. Renal nerve activity was elevated
in SHR at the age of 8 –10 wk (746, 941). Denervation of
the kidneys in young (4 – 8 wk old) SHR delayed the development of hypertension (606, 807, 1092, 1617) (775), due
at least in part to increased Na⫹ excretion (606, 1268).
Young (4 – 6 wk old) SHR had excessive preglomerular vasoconstriction that reduced RBF and GFR (43, 276, 1252,
1507). The lower GFR was ascribed to reductions in the
glomerular blood flow and the glomerular hydrostatic filtration coefficient (KUF) while the PGC was maintained by
increased afferent and efferent arteriolar resistances (335).
Hypertensive SHR between 12 and 16 wk of age have increased preglomerular vascular resistance that parallels the
increase in BP (42, 58, 358, 639, 704, 709, 1471), mediates
efficient autoregulation of RBF and GFR (8, 41, 107, 276,
640, 709, 1246, 1507), and maintains PGC in the normal
range (42, 58, 358, 704, 852, 1471) and normal glomerular
structure (787). The total number of glomeruli and mean
glomerular volume were similar in kidneys of SHR and
WKY at 4 wk of age (115). Albuminuria developed only
after ⬃20 wk of age.
Although the PGC was normal in 12- to 16-wk-old SHR
(1471), it tended to increase in some (1471), but not all
(394), studies by 36 mo, while the vascular and glomerular
morphology remained normal (1471). Thus glomerular hypertension can precede glomerular injury in SHR. Remarkably, in another study, the PGC of 15-mo-old SHR was
lower than age-matched WKY (394).
The administration of low doses of a CCB or an ACE inhibitor to SHR reduced their BP, increased their RBF and
454
GFR (412– 414, 567, 574, 765, 1056, 1098) and SNGFR
(435), and normalized their preglomerular and efferent arteriolar resistances (1056, 1098). Higher doses of a CCB
that blocked both L- and T-type VOCC abolished renal
autoregulation and rendered PGC highly dependent on BP
(365, 500, 852, 1056). These data suggest that the use of
CCBs to treat hypertension in patients with CKD is less
protective of renal function than ACE inhibitors, as confirmed in the African-American Study of Kidney Disease
(AASK) trial (909) and in experimental studies in rats (29,
365, 500, 503). Moreover, administration of an ACE inhibitor or an AT1 receptor blocker to young SHR caused a
predominant reduction in efferent arteriolar resistance,
thereby reducing PGC and the lower limit of renal autoregulation (852).
Young SHR have exaggerated renal vascular reactivity to
ANG II (44, 220, 222, 311, 787, 824, 825, 1409, 1542),
ATP (1434), catecholamines (787, 813, 1385, 1498), and
AVP (404) and attenuated vasodilation to PGE2, PGI2 (219,
223, 224, 716, 717), and agonists of dopamine D1 receptors
(225). Thus vasodilation and reduced buffering of vasoconstriction by GPCRs signaling and activation of the cAMP/
PKA pathway are defective in the renal vasculature of SHR
and contribute to the exaggerated vasoconstriction. The
exaggerated renal vascular reactivity to ANG II was largely
due to abnormal blunting by vasodilator PGs (217, 219,
221, 224, 716, 717), since the density of AT1 receptors in
the renal vasculature was similar in SHR and WKY (216,
220). However, vasodilation to ACh, sodium nitroprusside,
or bradykinin that is mediated by the cGMP/PKG pathway
was preserved or even exaggerated in young SHR (174,
225). Indeed, inhibition of NOS led to stronger increases in
RVR and reductions in RBF in adult SHR (10 –16 wk old)
than in WKY in some studies (96, 432, 853, 1203), implying enhanced regulation of the renal circulation by NO in
the SHR with established hypertension, whereas others reported a normal degree of vasoconstriction in adult and
aged (70 wk old) SHR (311, 432, 853).
Renal autoregulation operates normally in young and mature SHR. Unlike most other hypertensive models, the RBF
and GFR of SHR are very efficiently autoregulated with
maintained, or even an exaggerated, with strong influence
of myogenic and MD-TGF components throughout the established phase of hypertension (707, 1567). Steady-state
experiments demonstrated that SHR autoregulate their
RBF effectively with a normal plateau phase over a defined
range of RPP as they age from 4 – 6 wk (1252) to 10 –16 wk
(8, 42, 598, 640, 853, 1203, 1246, 1252, 1567) or even up
to 40 (708, 709, 852, 1567) to 70 wk (853). The plateau
phase of RBF autoregulation was unaffected by inhibition
of NO (853, 1203), the RAS (352, 1565), ET-1 and ETA
receptors (140), COX metabolites, ROS (815), or renal
nerve activity (708). Whereas autoregulation was not affected by endogenous ET-1 in normotensive animals (97,
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CARLSTRÖM ET AL.
140, 831), it was improved in SHR after short-term ETAreceptor blockade (140). However, in animals with established hypertension, these systems contribute to switching
the autoregulatory range to higher levels of RPP (705–707,
709, 852, 997, 1188, 1203, 1565–1567). The lower limit of
RPP for autoregulation was preserved in young hypertensive SHR (41, 1252).
Whereas SHR exhibited excellent autoregulation of renal
and outer cortical blood flow (704), JMN have increased
PGC with less efficient and more sluggish autoregulation.
Thus the PGC of JMN of SHR was 5 mmHg higher than
cortical nephrons at 10 wk of age and increased to 10
mmHg higher at 70 wk. The higher PGC corresponded with
an earlier development of glomerulosclerosis and with
larger diameters of glomerular capillaries in JMN (704).
Moreover, an abrupt step increase in RPP produced a rapid
adaptive increase in vascular resistance in the superficial
renal cortex but a slower, less complete response in the
juxtamedullary region (1240).
Autoregulation of medullary blood flow was well established in young SHR (1252). By 12–16 wk, the medullary
blood flow and the RIHP were reduced in SHR, accompanied by a rightward shift in the pressure-natriuresis relation
(412). At that age, autoregulation of medullary blood flow
was diminished during acute volume expansion, although
excellent autoregulation of whole kidney RBF persists
(352). Since medullary blood flow contributes ⬍10% to
total RBF, small changes may not be detected in measurements of total RBF. These findings are consistent with the
hypothesis of Cowley et al. (274) that an attenuation of
medullary blood flow autoregulation during volume expansion enhances the strength of the pressure-natriuresis relation and thereby modulates the level of BP, as was discussed
in section IIA2 and is illustrated in FIGURE 4B.
Medullary blood flow was especially sensitive to ANG II in
SHR during the development phase of hypertension (353).
ACE inhibition from 4 to 14 wk of age in volume-expanded
SHR attenuated the autoregulation of the medullary blood
flow despite a maintained autoregulation of RBF (352).
Administration of an AT1 receptor blocker to SHR between
4 and 12 wk of age reduced BP, increased medullary blood
flow, and reduced the number of pericytes surrounding vasa
recta capillaries (70). These treatments also impaired medullary blood flow autoregulation and increased the RIHP
which may contribute to the resetting of the pressure-natriuresis relationship to a lower level of RPP, and limiting the
development of hypertension (997, 1567). Indeed, most
studies employing infusions of CCBs, ACE inhibitors, tempol, lovastatin, or L-arginine concluded that SHR have a
reduced NO and a reduced medullary perfusion secondary
to increased medullary oxidative stress and that could account for a rightward resetting of the pressure-natriuresis
relationship and a higher ambient BP (276, 406, 412, 733,
872). These studies indicate NO is important in maintaining the medullary blood flow in SHR (96), and a reduction
in NO contributes to the lower medullary blood flow and
reduced pressure-natriuresis relation in SHR (872). Other
studies, however, suggested that NOS activity was elevated
in the renal medulla of SHR (585) and its inhibition produced a greater reduction in medullary blood flow in SHR
than in WKY (96). Collectively, these data suggest an important role for ANG II and the balance between ROS and
NO in the renal medulla during the development of hypertension in SHR. Indeed, several studies have reported enhanced interaction between ANG II, NO, and ROS in renal
autoregulation of SHR.
A strong MD-TGF response may contribute to the resilient
renal autoregulation in SHR. Young (6 wk old) SHR had
exaggerated MD-TGF response (333) that was attributed to
ANG II acting on AT1 receptors and to a vasoconstrictor
eicosanoid acting on TP receptors (138, 139). MD-TGF
activity reverted towards normal during established hypertension in adult SHR from the NIH/Chapel Hill colony
(333) and from some commercial suppliers (231), but remained exaggerated in adult (12–18 wk of age) SHR from
some other sources (894, 1587, 1592). However, there is
genetic heterogeneity between colonies of SHR, and especially WKY (848). Increased MD-TGF response in adult
SHR was attributed to AT1 receptor activation and oxidative stress (894, 1587, 1588, 1592) and weak buffering by
NO. Although SHR had increased renal cortical expression
of endothelial NOS and of MD nNOS, neither global inhibition of NOS nor relatively selective inhibition of nNOS
with 7-nitroindazole increased the MD-TGF in SHR as it
did in WKY (1464, 1587, 1588). On the other hand, peritubular capillary perfusion of tempol blunted MD-TGF activity more in SHR than WKY and restored the effect of
nNOS inhibition to enhance MD-TGF in SHR (1588). This
suggests that the JGA of hypertensive SHR produces excess
O2⫺ that bioinactivates MD-derived NO. O2⫺ in the JGA was
dependent on tubular fluid reabsorption activating NADPH oxidase NOX-2 in MD cells (448, 1592). Excess O2⫺
diminished dilation of juxtamedullary afferent arterioles by
neuronal NOS-derived NO in SHR but not in WKY (655).
Thus SHR generally have enhanced MD-TGF responses
that are related to oxidative stress in the JGA that inactivate
NO, thereby contributing to their efficient renal autoregulation.
Vasoconstriction from activation of MD-TGF can be propagated upstream along the afferent arteriole to reduce the
perfusion and the PGC in adjacent nephrons supplied by a
common cortical radial artery. The magnitude of such a
MD-TGF-initiated nephron-nephron interaction was stronger in SHR, implicating greater signal transduction (231).
Chon, Holstein-Rathlou, Marsh, and associates demonstrated that MD-TGF signaling to the parent glomerulus
caused oscillations in preglomerular vascular tone and PPT
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RENAL AUTOREGULATORY MECHANISMS
that were more time-variant and irregular in SHR, indicative of more complex coupling between MD-TGF and myogenic mechanisms (230, 244, 247, 625, 626, 1205, 1635,
1672). Thus studies of transfer function analysis generally
confirmed an enhanced MD-TGF, and perhaps myogenic
component, of autoregulation in SHR, which was consistent with increased ROS and reduced NO signaling in the
JGA.
Myogenic constriction of isolated perfused afferent arterioles was enhanced in both young and adult SHR (700,
1224). Thus exaggerated myogenic tone seems to be an
intrinsic functional abnormality evident during the development of hypertension in young SHR and not a consequence of long-standing hypertension in adult SHR.
The PP threshold for a myogenic contraction in the afferent
arteriole of the HNK was shifted 40 mmHg higher, while
the maximum myogenic constriction was preserved (593).
NOS inhibition lowered the threshold PP by 20 mmHg in
WKY and by 40 mmHg in SHR (15 wk old), whereas the
maximum myogenic response was augmented to a similar
degree in both strains (593). Thus NO can modulate the
myogenic response with different effects in the renal vasculature of SHR and WKY, perhaps due to different actions
on pre- and postglomerular arterioles. Perfusion of cortical
radial arteries and afferent arterioles of JMN with a physiological salt solution revealed enhanced myogenic contractions in SHR as young as 3– 4 wk of age (465, 672), which
were related to enhanced generation of a cytochrome P-450
metabolite (469, 672), presumably the vasoconstrictor 20HETE.
Oxidative stress is frequently associated with increased vascular reactivity, hypertension, and renal failure (1330,
1529). Prolonged tempol administration reduced BP in
SHR and shifted the pressure-natriuresis relationship to the
left (406, 1300, 1302, 1585). Tempol increased basal RBF
in hypertensive SHR, reduced exaggerated renal vascular
reactivity to ANG II, independent of NO, suggesting a direct effect of O2.⫺ on vascular responsiveness (311). Tempol quenching of O2.⫺ increased medullary blood flow
without perturbing RBF autoregulation in adult SHR (311,
406). Thus ROS apparently restrains renal and medullary
blood flow in the SHR without major effects on autoregulation.
The afferent arteriole of adult SHR has a fourfold increase
in ROS production by NOX-2 (1224). Thus, bioinactivation of NO by O2.⫺ in the JGA of SHR is sufficient to
prevent endogenous NO from blunting MD-TGF. It also
may explain the lack of effect of NOS inhibition to magnify
the renal myogenic response of SHR as it did in normotensive Long-Evans, Sprague-Dawley and Wistar rats (1569).
The strong myogenic response of young SHR was sufficient
456
to maintain RBF autoregulation after complete inhibition
of MD-TGF by ureteral obstruction (297).
Nevertheless, whereas NO is considered a strong modulator of the myogenic component of renal autoregulation in
normotensive rat strains, the modulation was weak or absent in the SHR (1569). This indicates a separation of the
role of NO to blunt vasoconstriction (evident in SHR and
normotensive strains) and to blunt the myogenic response
(absent in SHR).
Nevertheless, efficient RBF autoregulation and the myogenic response in SHR was preserved in the absence of
MD-TGF input during ureteral obstruction (297) and persisted after damage to mesangial cells by antithymocyte
antibodies in both SHR and WKY, whereas autoregulation
of GFR was attenuated (1564). Thus, although mesangial
cells can participate in the regulation of GFR, likely via
MD-TGF signaling, they do not seem to contribute to RBF
autoregulation, which, in their absence, is maintained by
enhanced myogenic tone.
SHR also have enhanced myogenic tone in nonrenal vessels
including cremaster muscle (389, 643, 644, 1359), basilar
(18), cerebral (127, 484, 564, 566, 725, 1469), mesenteric
(472, 714), and coronary arteries (458). Enhanced myogenic tone in these nonrenal vessels of SHR has been related
to increased Ca2⫹ entry due to depolarization of the plasma
membrane (564) and elevated VOCC activity (1359), perhaps secondary to reduced EM and reduced K⫹ channel
activity (1469). Also contributing were increased Ca2⫹ mobilization and Ca2⫹ sensitivity due to augmented Rho kinase activity (18, 725, 1164). Enhanced myogenic tone was
dependent on increased endothelial-derived ET-1 and
PGH2 (643, 644) and reduced NO (484), or other endothelial factors (458). The enhanced myogenic responses occurred without vascular remodeling (389) and were not
secondary to hypertension since they predated its onset
(127, 714, 1359). Mechanisms that enhanced myogenic
tone in these nonrenal vessels of SHR may also occur in the
renal microcirculation. However, these effects were specific
for resistance vessels since normal myogenic responses are
reported in larger conduit vessels from SHR (166, 167,
1084).
Remodeling (reorganization of the vessel wall components)
of small arteries can limit organ blood flow (425, 1044,
1322) and may contribute to exaggerated renal vasoconstriction. An increased cross-sectional area of the preglomerular arterial media was apparent in young SHR before
the development of hypertension (1385). Furthermore,
some of the second generation offspring of rats crossbred
between SHR and normotensive WKY had a narrowed afferent arteriole lumen diameter at 7 wk which predicted the
later development of high BP at 21–23 wk (1094, 1380).
This suggests that a narrowed renal afferent arteriole, as
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from remodeling, can contribute to the development of sustained hypertension. Most, but not all (1381), studies reported hypertrophic remodeling of the media with luminal
narrowing of cortical radial arteries of SHR that may persist
(33) or reverse with prolonged ACE inhibition (1379) and
may originate from enhanced sympathetic nerve activity
(1474). Thus a variable degree of genetically and neurally
determined remodeling of the afferent arteriole of the SHR
could restrict the transmission of BP into the kidneys,
thereby protecting the glomeruli from barotrauma and
maintaining the set-point for pressure-natriuresis at ambient level of RPP.
Other studies have identified increased wall thickness in
the arcuate and cortical radial arteries of 5- or 10-wk-old
SHR but not in the afferent arteriole at either age (33,
1385). The ratio of wall thickness to radius of the afferent arterioles in the inner and outer cortex was not different between SHR and WKY at 6 and 12 wk of age
(461). Another morphological study reported that afferent arterioles of 12-wk-old SHR had a smaller, not
larger, media cross-sectional area than age-matched
WKY (1381). Aged SHR have hypertrophy of the afferent arteriolar wall (882).
A hallmark of the SHR is excellent autoregulation of whole
kidney and outer cortical blood flow and PGC, which may
account for the paucity of glomerulosclerosis until up to 70
wk of age, despite increasing hypertension. Excessive NADPH oxidase-mediated O2⫺ production and downregulation of SOD and other antioxidant enzymes in the kidney of
SHR (12, 114, 212, 1649) likely contributes to the enhancement of myogenic and MD-TGF mechanisms. Much, but
not all, of the effects of O2⫺ in the JGA were secondary to
reduced NO activity (1588). However, as SHR age, their
cortical autoregulation eventually becomes slightly less
efficient and their outer cortical glomeruli develop modest glomerulosclerosis. The earlier impairment of autoregulation in JMN may account for their earlier development of glomerulosclerosis. Nonrenal resistance arterioles of SHR also generally display enhanced myogenic
tone, suggesting that it is a fundamental property of
VSMCs in this rat strain. Since augmented myogenic responses of renal and systemic microvessels of young SHR
precede the development of hypertension, they are likely
primary and genetically determined. A primary increase
in O2⫺ with bioinactivation of NO in the renal cortex and
medulla of the SHR could contribute to the excellent
autoregulation and reduction of transmission of BP into
the renal parenchyma. This should buffer the effects of
increased BP to raise medullary blood flow and RIHP in
the SHR, thereby attenuating the pressure natriuresis and
sustaining the hypertension on the one hand, yet protecting the renal parenchyma from the effects of hypertensive
barotrauma on the other.
2. Stroke-prone SHR
Stroke-prone SHR (SHR-SP) have a genetic predisposition
to stroke, a more rapid rise in BP, and a more pronounced
salt-sensitivity than SHR (1048, 1116). They were normotensive at 4 wk of age and developed hypertension before 9
wk (908, 1049). Kidneys of SHR-SP required a higher BP
than WKY to excrete a given amount of salt and water
(1049). Marked proteinuria was evident by 12–16 wk of
age (1055, 1478). Glomerulosclerosis was present by 24 wk
of age (1055). At 15 mo, the kidneys of SHR-SP on a normal-salt diet displayed reduced GFR, arterial wall hypertrophy and sclerosis, glomerulopathy, and tubular interstitial
injury, all of which were prevented by normalization of the
BP during ACE inhibition since 4 wk of age (908). Remarakbly, this nephroprotection was associated with almost a
doubling of the lifespan.
When given 1– 4% NaCl to drink, they develop severe hypertension and usually die from stroke within 14 –20 wk.
Transplantation of a kidney from an SHR-SP into an SHR
accelerated the rise of BP, the reduction of RBF and GFR
(1049), and the development of renal damage (498). Thus
SHR-SP kidneys have a genetic propensity to cause hypertension and also an enhanced susceptibility to hypertensive
injury (261).
The basal RBF and GFR were reduced and the RVR increased in hypertensive 9- or 12-wk-old SHR-SP relative to
normotensive controls (1049, 1055). The BP and the RBF
increased with a high-salt diet (8). The renal vasculature of
4-, 8-, and 16-wk-old SHR-SP was hyperresponsive to ANG
II, AVP, NE (94, 1050), and ET-1 but not to AVP (457).
Dopamine D1 receptor stimulation produced enhanced vasodilation via PKC/cAMP signaling in intrarenal arteries of
SHR-SP (456). Acute CCB reduced BP and increased RBF
without affecting GFR (1031). Six-month-old SHR-SP
given CCB for 3 mo had reduced BP with attenuation of the
development of glomerulosclerosis, reduced vascular wall
thickness, less glomerular and interstitial fibrosis, and increased glomerular volume (692). Similar beneficial structural effects were observed when BP was reduced by blockade of adrenoceptors. ETA receptor blockade starting at 8
wk of age attenuated progressive decline in renal function
(measured as creatinine clearance), delayed proteinuria,
and doubled the life-span of both male and female SHR-SP
on a 4% NaCl intake (1478). Such functional changes took
place even though antagonism of ETA receptors had little or
no effect on BP, as systolic BP (tail-cuff) rose to 240 mmHg
in both treated and untreated animals. AT1 receptor blockade starting at 12 wk reduced BP, normalized RBF and GFR
in SHR-SP to WKY levels, and reduced the index of glomerulosclerosis (1055). Prolonged TP receptor antagonism
from either 7 or 16 wk of age had no effect on BP, development of proteinuria, cerebrovascular lesions, or stroke in
SHR SP drinking 1% NaCl (741).
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RENAL AUTOREGULATORY MECHANISMS
The steady-state values and the autoregulation of total and
cortical blood flow of SHR-SP were well maintained during
normal salt diet (8, 94, 646), but the autoregulation of
medullary blood flow was weak (646). As expected, a CCB
abolished autoregulation of renal cortical blood flow (646).
Another study reported moderate efficiency of RBF autoregulation with an AI of 0.5 in 9-wk-old SHR-SP (1049).
Transfer function analysis confirmed a well-preserved renal
autoregulation in conscious 12-wk-old SHR-SP consuming
a normal-salt diet, but less efficient autoregulation after an
8% NaCl diet for 3–5 days (8). The sharp increase in BP and
the loss of renal autoregulation may contribute to the severe
salt-dependent renal damage (8). Enhanced renal vasoconstriction and MD-TGF activity in SHR-SP nephrons were
normalized by acute renal denervation (1562).
Cortical radial arteries of the HNK preparation retained a
normal myogenic response in young SHR-SP but an increased PP threshold (586). Hayashi et al. (587) reported
that the myogenic reactivity of the cortical radial artery of
the HNK increased along the length of the vessel and that
SHR-SP exhibited augmented responsiveness of the intermediate but not the distal segment. This was evident by
constriction at a lower threshold PP and greater maximum
reductions in diameter compared with WKY.
Cerebral arteries of 12-wk-old SHR-SP displayed medial
hypertrophy and remodeling, together with attenuated
myogenic response (715). Moreover, loss of cerebral blood
flow autoregulation was observed prior to the event of
stroke (1387). Interestingly, RAS inhibition preserved cerebral autoregulation and the myogenic response and delayed
the onset of stroke (1133, 1134, 1559), largely independently of BP (1384). Thus a high-salt diet impairs autoregulation of the renal and cerebral blood flow of SHR-SP that
likely contributes to the severe hypertensive renal damage
and the propensity for stroke.
3. Dahl salt-sensitive rat
Three-week-old Dahl salt-sensitive (DS) and Dahl salt-resistant (DR) rats, when nephrogenesis is still ongoing, were
normotensive when receiving a low-salt diet (742), but this
has not been studied by telemetry in conscious rats. Renal
injuries developed before the loss of dynamic renal autoregulation (769). Indeed, prehypertensive DS rats of the JR (J
Rapp) strain already had albuminuria, and glomerular
damage accelerated once hypertension was established
(1418). Moreover, the GFR of DS rats, even when fed a
low-salt diet, was reduced by 6 wk (1526). When fed a
high-salt diet, the BP of DS rats increased and both RBF and
GFR decreased (642) leading to glomerular hypertension,
progressive proteinuria, and renal insufficiency (229, 1208,
1418). This was accompanied by intimal thickening and
fibrinoid necrosis (deposits of immune complexes and fibrin) with hyperplasia and necrotizing arteritis (i.e., inflammation of the vascular wall) of the large preglomerular
458
vessels (551, 788), all characteristic for human malignant
hypertension. Medullary interstitial fibrosis and tubular necrosis were also severe (278). Many DS rats died after 4 – 8
wk treatment with a high-salt diet (229, 1208). Thus the DS
rat has severe structural and functional changes in its renal
vasculature that are apparent very early in life even when
fed a low-salt diet to prevent hypertension. A switch to a
high-salt diet leads to malignant hypertension with pronounced renal damage.
Kidney cross-transplantation between DS and DR rats demonstrated that the genotype of the donor kidney determined
the BP of the recipient rat (259, 292). Single chromosome
substitutions from normotensive BN into DS rats demonstrated that the development of hypertension and proteinuria were determined by genes on chromosomes 1, 5, 7, 8,
13, and 18 in males and on chromosomes 1 and 5 in females, although several chromosomes in males and females
affected the development of albuminuria without affecting
BP (988). Transfer of the region of chromosome 5 that
contained the gene for cytochrome P-450 – 4A from Lewis
into male DS rats increased 20-HETE in the outer medulla
and attenuated hypertension and renal injury (1611). These
responses may relate to the natriuretic actions of 20-HETE
(1250). Thus multiple sex-specific genes contribute to hypertension in DS rats. Since some of these differ from those
determining CKD, there is a genetically determined dissociation of renal damage from hypertension, but the specific
genes involved have yet to be identified. This is somewhat
analogous to African-Americans who have a much increased risk of developing hypertensive renal damage (nephrosclerosis), yet lowering their BP below normal failed to
slow the progressive loss of their GFR (13), perhaps because
of inherited alleles from genes such as apolipoprotein L-1
(APOL-1) or the nonmuscle myosin heavy chain 9 (MYH9)
that confer genetic risk for renal damage in African-Americans specifically (442, 909, 1156).
RBF and GFR were similar initially in prehypertensive and
moderately hypertensive DS and DR rats (1255), but became reduced in DS rats with the development of hypertension and proteinuria during salt loading (229, 259, 769,
1244, 1445). The renal vasculature of DS rats was hyperresponsive to vasoconstriction by ANG II, ET-1, and NE
during a high-salt diet (517, 1366) but failed to dilate with
atrial natriuretic peptide (ANP) or NO (1366). This vascular phenotype was genetically determined since it was corrected in consomic DS rats receiving chromosome 13 from
BN rats (278). The development of hypertension in DS rats
was preceded by a shift in the pressure-natriuresis relationship toward a higher BP (1244, 1251), implying a renal
mechanism and Na⫹ retention. Normotensive DR and DS
rats fed a low-salt diet have effective steady-state whole
kidney and outer cortical and medullary blood flow autoregulation (1251) which were maintained in DS receiving a
high-salt diet in some (1244, 1445) but not all studies
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(1251). The plateau phase of RBF autoregulation was maintained, although the inflection point for cortical blood flow
autoregulation was elevated ⬃30 – 40 mmHg (1244, 1251,
1445). However, others studies reported that neither the
renal medullary nor the papillary blood flow was autoregulated in either DS or DR rats whether fed low-salt (1244,
1251, 1366) or high-salt diets (1251), which suggests that
the salt-sensitive hypertension in DS rats is independent of
changes in medullary autoregulation. Nevertheless, another
study reported a high-salt diet fed to DS rats impaired RBF
autoregulation and related this to AT1 receptor-mediated
ROS production (1286). Moreover, frequency analysis of
dynamic RBF autoregulation in DS rats revealed normal
autoregulatory pattern of transfer gain when normotensive
on a low-salt diet, but a progressive decline in the efficacy of
autoregulation when hypertension was induced by a highsalt diet, especially when initiated 2 wk after weaning (769).
The absence of dynamic RBF autoregulation in the DS rats
with early-onset hypertension was evident as both the myogenic and TGF contributions were defective. The observation that vascular injury preceded the loss of whole kidney
autoregulation led to the conclusion that the impaired autoregulation was the result, not the cause, of the renal failure (769). This may explain the variable reports of renal
autoregulation described above.
Oxidative stress contributes to vascular damage and abnormal renal hemodynamics and Na⫹ excretion in DS rats.
NADPH oxidase was overexpressed in the renal cortex of
DS rats fed a high-salt diet (449). DS rats have enhanced O2⫺
production in the outer medullary TAL of Henle’s loop that
reduced the bioavailability of medullary NO (1030, 1453).
This could reduce medullary perfusion and attenuate the
pressure-natriuresis (424). Indeed, restoration of NO in DS
rats normalized the medullary blood flow and prevented
hypertension (1014).
MD-TGF was normal in DS and DR rats even on a high-salt
diet (770). A mathematical model led to the conclusion that
hypertensive DS rats have a severely reduced efficiency of
the myogenic mechanism, whereas the MD-TGF response
was normal (811). However, hypertensive DS rats also have
an enhanced CT-GF response that buffers renal vasoconstriction (1555). This may contribute to vasodilation, increased PGC, and glomerular damage in hypertensive DS
rats fed with high-salt diet. Afferent arterioles in the HNK
preparation of both normotensive and hypertensive DS rats
have greatly diminished myogenic responsiveness and a
higher threshold PP (589, 1436). The preglomerular resistance vessels of normotensive DS rats fed a low-salt diet
have an enhanced sensitivity to inhibition of myogenic responses by a CCB, suggesting reduced activity or density of
L-type VOCCs (1436). Both NO- and EDHF-mediated
components of ACh-induced afferent arteriolar dilation
were attenuated in DS rats by enhanced ROS (1145).
Reduced renal vascular production of 20-HETE accounted
for the impaired myogenic and MD-TGF responses of the
afferent arteriole and the weak autoregulation of RBF and
PGC (463, 1220).
Cerebral arteries from salt-fed hypertensive DS rats normally have a fast myogenic response. This was maintained
in one study (56), but attenuated in another report, thereby
leading to hypertensive encephalopathy, seizures, and disruption of the blood-brain barrier (600, 1164, 1386). The
myogenic response of skeletal muscle arterioles that is normally slow and modest was reduced, but the gracilis arteries
of hypertensive DS rats maintained myogenic tone related
to 20-HETE production that inhibited KCa channels and
reduced EM (446).
Knockdown of TGF-␤1 expression slowed the progression
of proteinuria, glomerulosclerosis, and renal interstitial fibrosis in DS rats fed a high-salt diet independently of
changes in BP (226). Prolonged blockade of TGF-␤1 increased the medullary blood flow and reduced BP modestly
(293). This suggests that the development of hypertension,
glomerular and tubular injury, and vasoconstriction all may
depend on overproduction of this growth factor in the renal
medulla of DS rats.
In summary, renal cortical blood flow autoregulation is well
maintained in normotensive DS and DR rats fed a low-salt
diet and in early hypertensive DS rats during increased salt
intake. Since the impairment of autoregulation follows the
development of renal injury, which indeed is apparent soon
after birth, it is likely the result, not the cause, of the renal
failure. The eventual loss of renal autoregulation is related
to impaired myogenic responses in hypertensive DS rats
consuming salt since MD-TGF activity is maintained. These
rats tend to have impaired cerebral arteriolar myogenic
tone, which probably contributes to their development of
hypertensive encephalopathy. The finding of preserved
myogenic responses in skeletal muscle arterioles suggests
that the severely impaired responses in most studies of renal
vessels is not due to a generalized failure of myogenic mechanisms and is consistent with a secondary response to renal
vascular and parenchymal damage.
4. Goldblatt renovascular hypertension
In 1937, Goldblatt (476) reported that hypertension commonly developed after constriction of one main renal artery
to reduce RPP (two-kidney, one-clip or 2K,1C model). This
models renovascular hypertension from unilateral renal artery stenosis. The GFR was similar in the two kidneys of
rats with moderate, early 2K,1C hypertension with no obvious renal pathology (1410). Hypertension and renal vasoconstriction are related to an activated RAS since AT1A
receptor deficient mice develop little hypertension after the
clipping of one renal artery (206, 208), and blockade of the
RAS or AT1 receptors in rats reduces the BP and produces
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RENAL AUTOREGULATORY MECHANISMS
marked vasodilation of the nonclipped kidney (209, 210,
649, 650, 669, 1186, 1566), similar to CCB blockade
(1186). In contrast, the clipped kidney sustains a further
reduction in its RBF and GFR, suggesting either that its
autoregulation is severely impaired or that the RPP beyond
the clip is reduced below the autoregulatory range. An ACE
inhibitor given to rats with 2K,1C hypertension reduced the
BP, RBF, PGC, and afferent and efferent arteriolar resistances in the clipped kidneys (310), whereas a CCB reduced
afferent arteriolar resistance selectively (310).
Micropuncture studies of superficial nephrons in moderately hypertensive 2K,1C rats reported that the nonclipped
kidney has well maintained or increased SNGBF, SNGFR,
and PGC, findings consistent with a predominant increase in
preglomerular vascular resistance (308, 452). However, in
others, the PGC was elevated and the SNGBF and SNGFR
were reduced, suggesting a reduced KUF (452, 1410). The
SNGBF, SNGFR, and PGC were reduced in the clipped kidney of 2K,1C rats, implying increased preglomerular vascular resistance from the clip and/or the vasculature (1336 –
1338).
Constriction of one main renal artery and removal of the
other kidney (one-kidney, one-clip or 1K,1C model) also
causes hypertension, but this model is less dependent on the
RAS and is distinctly salt sensitive. The 1K,1C is a model of
renal transplant stenosis or bilateral renal artery stenosis.
These clinical conditions resemble the 1K,1C model since
all lack a “normal” contralateral kidney to correct renal salt
retention by the clipped kidney. The clipped kidney of
1K,1C rats had reduced SNGBF and SNGFR with unchanged PGC due to a preferential increase in efferent arteriolar resistance (1336).
Dogs (1047) and some rats (705, 707, 1365, 1566) with
2K,1C hypertension have maintained RBF and GFR autoregulation in the nonclipped kidney, although other studies
in rats have reported weak autoregulation (1188, 1404,
1494) that was improved by NOS inhibition (1494). Blockade of AT1 receptors in 2K,1C hypertensive rats did not
affect RBF autoregulation in the nonclipped kidney but
abolished GFR autoregulation (1566), presumably because
of a reduced efferent arteriolar resistance. Autoregulation
of renal cortical perfusion of the nonclipped kidney of
2K,1C hypertensive rats was relatively resistant to blockade
by a CCB (646), suggesting upregulation of L-type VOCCs.
The clipped kidney has a weak, or even nonexistent, autoregulation of RBF (705). The post-clip kidney and its blood
vessels were protected from barotrauma, whereas there
were extensive glomerular and vascular injuries in the contralateral nonclipped kidney (1365).
yet maintained NO vasodilation (684), indicating a selective impairment of autoregulation. The myogenic response
of afferent arterioles in HNK nonclipped kidneys of rats
with 2K,1C hypertension was blunted and shifted to higher
levels of PP (589).
Increased NO production by the nonclipped kidney (318,
1363) impaired its RBF autoregulation since this was normalized by NOS inhibition (1494), whereas reduced EET
production contributed to renal vasoconstriction. However, restoring EETs did not restore autoregulation (1404),
indicating that they were not the cause of defective renal
autoregulation. Similarly, 20-HETE participated in basal
vasoconstriction, but did not account for the attenuated
autoregulation in the unclipped kidney of 2K,1C rats. Thus
increased levels of NO could account for some of the
changes in autoregulatory efficiency, whereas altered production of EETs and 20-HETE are not implicated.
The MD-TGF response in the nonclipped kidney of 2K,1C
rats generally was normal or enhanced (134, 648). However, MD-TGF responses in the nonclipped kidneys of
2K,1C rats early after developing hypertension were attenuated despite an activated RAS (1191, 1314, 1317). The
MD-TGF response in the nonclipped kidneys was enhanced
greatly after NOS inhibition (1491, 1494). MD-TGF in the
clipped kidney was very hard to measure, but was normalized shortly after removing the renal artery clip (1191,
1317). MD-TGF was attenuated severely in the solitary
kidney of 1K,1C rats (1187).
Dynamic analysis of proximal tubular pressure in the nonclipped kidney of 2K,1C rats during the first week of hypertension revealed normal MD-TGF oscillations. As the hypertension progresses, these oscillations transitioned into
deterministic chaos, similar to that found in adult SHR
(1635). To our knowledge, renal vascular admittance has
not been analyzed across the full-frequency spectrum in
animal models of renovascular hypertension.
In summary, results on the efficacy of steady-state autoregulation of RBF in the nonclipped kidney of 2K,1C hypertensive rats are quite mixed, with roughly equal numbers
reporting that it is well-maintained or impaired. The reason
for this disparity is not known. Likewise, reports of MDTGF responses in nonclipped kidneys have varied from normal to markedly impaired. The MD-TGF activity appears
to be the outcome of an enhancement due to ATI-receptor
activation from renin released by the clipped kidney that is
offset by increased NO. Autoregulation is weak or absent in
the clipped kidneys, perhaps because the RPP is at, or below, the lower limit of autoregulation.
5. ANG II-induced hypertension
Medullary blood flow autoregulation in the nonclipped kidney was impaired (646), and its preglomerular juxtamedullary blood vessels failed to vasodilate during reduced RPP
460
Prolonged infusion of ANG II at an initially subpressor rate
gradually increases BP, oxidative stress, RVR, inflamma-
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CARLSTRÖM ET AL.
tion, and renal parenchymal injury in association with renal
vasoconstriction and an early phase of Na⫹ retention (492).
The degree of hypertension and renal injuries are related to
the dose of ANG II used, choice of species (rats vs mice), and
the duration of treatment. Cross-transplantation studies in
AT1 receptor-deficient mice demonstrated that the major
prohypertensive actions of ANG II are on renal AT1 receptors (281). Development of hypertension was prevented by
an AT1 receptor blocker (1550). ANG II receptors, in particular AT1, in the vasculature are usually downregulated
by high levels of ANG II (15, 77, 91, 526, 1266). Renal
vascular AT1 receptors expression was reduced in ANG
II-induced hypertension (39).
Most studies of renal function have been conducted during
the established phase of hypertension after 1 or 2 wk of
ANG II infusion. At this time point, the Na⫹ excretion,
RBF, and GFR were normal or modestly reduced (207, 652,
1088). RVR is consistently increased. The SNGBF, SNGFR,
and KUF were reduced and afferent and efferent arteriolar
resistances increased (436). PGC was increased during albuminuria (1008). Pressure natriuresis in ANG II-induced hypertension was reset to a higher RPP despite efficient autoregulation of medullary blood flow (1516, 1549).
Blockade of AT1 receptors in ANG II-induced hypertensive
rats reduced BP and increased RBF and cortical blood flow,
GFR, and Na⫹ excretion (1550). Reactivity of afferent arterioles of JMN to ANG II, but not PE, was increased after
1 or 2 wk of ANG II infusion (670). The exaggerated response depended on the presence of renal nerves (660) and
increased inactivation of EETs by soluble epoxide hydrolase (1662). Reactivity of afferent arterioles of JMN to ATP
by P2X1 receptors was reduced after 1 or 2 wk of ANG II
infusion (1661).
ANG II-induced hypertension and renal vasoconstriction
are dependent on enhanced ROS production by NADPH
oxidase (1015, 1128, 1584), impaired renal cortical NOS
activity (241, 242, 1025), and reduced renal medullary NO
production (1432). Although COX inhibition has little impact (483), hypertension and renal vasoconstriction were
less in TP receptor gene-deleted mice (441, 780), implicating involvement of a vasoconstrictor prostanoid, perhaps
TxA2, acting on TP receptors.
Prolonged infusion of ANG II increased NOS activity in the
renal cortex, with enhanced expression of eNOS and
nNOS, but no change in NOS activity in the renal medulla
(241). Accordingly, NOS inhibition produced greater renal
vasoconstriction with greater reductions in RBF and cortical blood flow (242). The authors concluded that a compensatory increase in NO helps to counteract the vasoconstrictor influence of ANG II and thus maintains RBF and
cortical perfusion.
The normal renal vasoconstriction after inhibition of nNOS
was lost in ANG II-infused rats (207). A CCB normalized
BP, RVR, GFR, and Na⫹ excretion in rats with ANG IIinduced hypertension (652). Vascular remodeling may contribute to ANG II-induced hypertension (373). ANG II produced less hypertension in adenosine A1 receptor-deficient
mice (455). Enhanced afferent arteriolar responses to ANG
II in hypertensive wild-type mice were reduced by tempol.
Contractions in arterioles lacking the A1 receptor were
weaker and not attenuated by tempol, suggesting that A1
signaling may modulate ANG II-mediated contraction or
oxidative stress.
RBF autoregulation was impaired, whereas medullary
autoregulation was preserved in nondiuretic ANG II-infused rats (1549). One study of ANG II-induced hypertension in UNx rats reported normal autoregulatory responses of the afferent arteriole of JMN whether or not
the kidney was denervated (660). Other investigators reported that the autoregulatory response of the cortical
radial artery and afferent arteriole in the JMN preparation was attenuated 14 days after ANG II-induced hypertension (198, 670, 689). This was related to vascular
injury (198, 1029) and activation of ET-1 receptors. Normalization of BP by prolonged AT1 receptor blockade or
by triple therapy (hydralazine, hydrochlorothiazide, and
reserpine) restored autoregulation of afferent arterioles
(689). RBF autoregulation was impaired during ANG
II-induced hypertension (AI increased from 0.04 to 0.66),
which was normalized by blockade of P2Y12 receptors
(1132). Administration of the anti-inflammatory agent
pentosan polysulfate for 14 days restored autoregulation
of afferent arterioles of JMN in ANG II hypertensive rats
via normalization of P2X1 receptor activation by ATP
during sustained hypertension (520). Other studies on
superficial nephrons reported augmented P2X1-mediated
constriction of afferent and efferent arterioles in rats
with ANG II-induced hypertension while P2X1 receptor
density was normal, perhaps due to inhibition of NO
production (436).
In contrast, UNx rats infused with ANG II for 2 wk have
normal afferent arteriolar myogenic responses of JMN
(660), as do cortical afferent arterioles from ANG II-infused
mice studied ex vivo (864). Afferent arterioles from ANG
II-infused rabbits have enhanced contractions to ANG II
despite a twofold downregulation of mRNA for AT1 receptors (1552). This was offset by a fivefold upregulation of
mRNAs for p22phox (1552). In agreement, enhanced arteriolar reactivity to ANG II was absent in mice with NOX-2
deficiency (182, 184). Moreover, isolated cortical radial
arteries of ANG II-infused mice lacking regulator of G protein signaling-2 had stronger myogenic tone and constrictor
responses to ANG II, probably by sensitizing AT1-receptor
signaling (604).
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RENAL AUTOREGULATORY MECHANISMS
Admittance transfer function in anesthetized ANG II-infused rats demonstrated impaired myogenic and MD-TGF
components of renal autoregulation independent of ET-1
(1272) but magnified by a high-salt diet that increased ROS
(1273). However, a careful study of dynamic autoregulation in conscious ANG II-infused rats reported a clearly
enhanced myogenic mechanism and reduced transmission
of BP fluctuations to the kidney (1193), whereas the MDTGF signature was unaltered. Likewise, long-term ANG II
infusion in conscious dogs potentiated the myogenic resonance peak (755). Thus these studies in conscious animals
with prolonged ANG II infusion may explain the relatively
modest degree of hypertensive glomerular injury since increased myogenic responses were lost under anesthesia.
ANG II is known to stimulate oxidative stress and increase
NADPH oxidase expression in the kidney (211, 455, 578).
Tempol normalized the vascular O2⫺ production and reduced BP without affecting the RBF of ANG II-infused rats
(1088). Oxidative stress is thought to play an important
role in the regulation of medullary blood flow and pressure
natriuresis (273, 964, 1099, 1670).
ANG II can activate T cells that release cytokines to promote oxidative stress, inflammation, renal vasoconstriction, and Na⫹ retention, all of which are prohypertensive
(534, 579). As observed with an AT1 receptor blocker, administration of the anti-inflammatory agent mycophenolate
mofetil during ANG II infusion reduced BP, renal vasoconstriction, and renal interstitial inflammation (439).
Although the MD-TGF was augmented by short-term ANG
II infusions (1012, 1077) and usually attenuated by pharmacological or genetic inhibition of the RAS and AT1 receptors (see sect. VIA), prolonged slow-pressor infusion of
ANG II did not change MD-TGF at normal tubular fluid
flow (1095). During chronic ANG II infusion, there was a
complex regulation of MD-TGF by a vasoconstrictor prostanoid that activated TP receptors and by ROS that impaired NO signaling in the JGA and by reduced expression
of AT1 receptors (39). COX-1 products enhanced MD-TGF
by activation of TP receptors that elevated ROS in the kidney (137, 1082, 1083, 1581, 1593), whereas COX-2 products attenuated MD-TGF in ANG II-infused mice (39).
ANG II-induced hypertension depended in part on activation of TP receptors (780). Increased MD-TGF during prolonged ANG II infusion was related to a reduced blunting
by MD-derived NO because of enhanced O2⫺ (133, 184,
659, 1608). Small interference RNA knockdown of p22phox
reduced ROS and MD-TGF activity by 50% in ANG IIinfused rats, thereby linking ROS to enhanced MD-TGF
(1095). P2X1 receptor signaling in the kidney (436) and
preglomerular vessels of JMN was impaired by inflammation caused by ANG II infusion (520, 686, 1661). Prevention of inflammation improved autoregulation, apparently
by normalizing MD-TGF activity (686, 1661).
462
In summary, steady-state RBF autoregulation is attenuated
in most studies of ANG II-induced hypertension, although
medullary blood flow and its autoregulation are generally
well maintained. Myogenic tone is enhanced in intact kidneys of conscious animals, but not in isolated arterioles,
suggesting that a reduced MD-derived NO may enhance
responses in intact kidneys. MD-TGF is normal or exaggerated, likely the outcome of enhanced O2⫺ generated in the
JGA in response to vasoconstrictor COX-1 metabolites that
activate TP receptors and decrease NO activity. However,
MD-TGF is attenuated in JMN, perhaps related to inflammation impairing P2X1 receptor signaling. The reasons for
the differential effects of ANG II on MD-TGF responses of
superficial and deep nephrons and the variable effects of
ROS to dampen or enhance myogenic responses are not yet
resolved. Thus there are major hemodynamic differences in
the response to chronic versus acute activation of the RAS
and perhaps the balance of NO and oxidative stress. Longterm ANG II stimulates ROS production that impairs the
bioavailability of NO and enhances production of a vasoconstrictor prostanoid that activates TP receptors. These
are offset by adaptive reductions of AT receptor expression
and structural changes of the vascular wall.
6. DOCA-salt hypertension
Prolonged administration of the mineralocorticosteroid deoxycorticosterone acetate (DOCA) and a high-salt diet
(e.g., 1% NaCl) have usually been combined with UNx to
model volume-expanded, low plasma renin activity (PRA)
hypertension similar to human primary hyperaldosteronism. This model is dependent on increased ET-1 production
in blood vessels and kidneys (1291). DOCA-salt mice have
a rightward shift in the pressure-natriuresis relation (512).
UNx rats with DOCA-salt hypertension have increased PGC
and develop proteinuria and focal glomerulosclerosis (361,
363). Nonspecific antihypertensive therapy (hydrochlorothiazide, hydralazine, and reserpine) reduced BP in
DOCA-salt rats but failed to prevent elevated PGC, proteinuria, or glomerular injury (361). Combined blockade of Tand L-type VOCCs decreased BP and PGC and reduced proteinuria and glomerular lesions without affecting the RAS
(75, 767), whereas selective antagonists of L-type VOCCs
also decreased the BP but stimulated the RAS and failed to
prevent proteinuria or glomerular lesions (75, 365, 767).
This finding in hypertensive animals is perplexing in view of
the reported absence of T-type channels in glomerular arterioles of normotensive rats (1388). However, another study
reported that an L-type CCB was more effective than ACE
inhibition in reducing the BP, proteinuria, and glomerular
pathology, although both treatments reduced the PGC
(364). A sharp fall in BP sufficient to reduce PGC may account for the protective effects of the CCB in this study.
Dietary Ca2⫹ supplementation reduced PGC, proteinuria,
and renal injury without changing the BP (359). Thus an
elevated PGC and the RAS are more important than hyper-
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CARLSTRÖM ET AL.
tension in predicting proteinuria and renal damage in the
DOCA-salt model.
Basal RBF and GFR are normal or reduced in DOCA-salt
rats and dogs (45, 540, 540, 674, 969, 1047, 1047, 1253).
There was a maintained plateau phase of RBF autoregulation, with either a normal (45) or a 20 mmHg increase in its
lower limit (674). RBF autoregulation in dogs with DOCAsalt hypertension was well preserved and independent of
renal sympathetic nerves or PGs (1420), but GFR was
poorly autoregulated (550). Neither RBF nor GFR was autoregulated in the isolated perfused kidney of DOCA-salt
dogs (764), but autoregulation generally is less efficient in
this preparation. The RBF was less efficiently autoregulated
in DOCA-salt hypertensive Yucatan miniature swine, but
again there was even less complete autoregulation of GFR
(1647). RBF and renal cortical blood flow were well autoregulated in DOCA-salt mice, and surprisingly, medullary
blood flow was more efficiently autoregulated in DOCAsalt than in control mice (512).
Some studies of DOCA-salt rats reported attenuated MDTGF (1040, 1315) and autoregulation of SNGFR (1022),
whereas others reported that the autoregulation of GFR
and SNGFR were well maintained despite inhibition the
MD-TGF (540). The findings in several studies of DOCAsalt hypertensive rats, dogs, or swine that the GFR was less
well autoregulated than the RBF suggest a reduced efferent
arteriolar resistance due to the strongly suppressed RAS.
Vascular O2⫺ production was increased in DOCA-salt hypertensive rats (1391). Antioxidants (100, 968) or inhibition of NADPH oxidase (641, 735) reduced BP, vascular
O2⫺, and renal damage. ET-1 production was increased in
the vasculature of DOCA-salt hypertensive rats (227,
1292), and selective blockade of ETA receptors reduced BP,
vascular O2⫺ generation, and RVR, but did not always improve renal damage (14, 175, 938, 1264). ETB receptors
may provide a protective function. Rats lacking ETB receptors have exaggerated vascular and renal pathology (986)
accompanied by reduced NO production (620) that may
underlie the enhanced vasoconstriction of their afferent arterioles (1470). However, others have ascribed the renal
vasoconstriction and hypertension to enhanced activity of
the renal sympathetic nerves (719, 776), since renal denervation delayed the development of hypertension and increased Na⫹ excretion (775) or to inflammation since immunosuppression preserved GFR and reduced proteinuria
in DOCA-salt hypertension (124). Another study implicated purinergic signaling since P2X7 receptor-deficient
DOCA-salt mice were less hypertensive and infiltration of
immune cells and renal injuries were blunted (732).
In summary, DOCA-salt is a model of low-renin, volumeexpanded hypertension that resembles human primary hyperaldosteronism. Factors contributing to hypertension, re-
nal vasoconstriction, and renal damage include oxidative
stress, NO deficiency, inflammation, enhanced P2X7 and
ETA but reduced ETB receptor signaling, and enhanced renal nerve activity. Despite the renal vasoconstriction and
abnormal receptor signaling, RBF autoregulation is well
maintained in most studies, albeit GFR autoregulation is
less efficient, likely reflecting a diminished efferent arteriolar resistance in this low renin-angiotensin model. The preservation of RBF autoregulation despite a markedly attenuated MD-TGF response suggests an intact or enhanced
myogenic mechanism, but this has not been studied specifically.
7. FH hypertensive rat
The FH rat is a genetic, renin-dependent, model of systemic
and glomerular hypertension that develops progressive albuminuria and spontaneous focal and segmental glomerulosclerosis (FSGS) that shortens its lifespan (841). It resembles progressive loss of function in humans with CKD. Mild
hypertension and increased PGC developed by 8 wk (843,
1371), proteinuria and enhanced myogenic contraction of
small mesenteric artery by 20 wk (1527), FSGS and proteinuria by 2– 6 mo, and severe hypertension and CKD with
malignant nephrosclerosis by 1 yr (294, 840, 842, 843,
1202, 1527, 1579). The FH rats are reported to die of renal
failure at sea level, whereas at altitude (e.g., Denver-raised
FH rats) they die of pulmonary hypertension, which has
been characterized by a deficiency of pulmonary eNOS and
abnormal vascular growth (878).
Studies in FH rats, before and after appearance of renal
injury, demonstrated that attenuated renal myogenic responses in 7-wk-old FH rats preceded glomerulosclerosis
and proteinuria (1102). Increased renal cortical and medullary blood flow and PGC were related to a low ratio of
afferent to efferent arteriolar resistance. Autoregulation of
RBF, cortical perfusion, and PGC were impaired markedly
in adult FH rats (1522, 1534). Prolonged ACE inhibition
largely prevented the systemic and glomerular hypertension
and renal damage (1534, 1535).
Isolated, perfused cortical radial arteries from young FH
rats constricted weakly or even dilated with increased PP
(1102, 1522, 1527). This severe defect, or even absence, of
myogenic contraction was considered renal specific since
those contracted normally to PE (1534) and the myogenic
responses of isolated mesenteric arteries and the aorta were
preserved (1102, 1527). This suggested a profound defect in
renal arteriolar mechanosensitivity or mechanotransduction. On the other hand, cortical radial arteries and afferent
arterioles in the HNK preparation of FH rats had nonselective impairment in reactivity to PP and to ANG II (1523).
Micropuncture studies of FH rats with mild FSGS reported
normal MD-TGF activity that increased with age and was
independent of ANG II (1534). An increased expression of
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RENAL AUTOREGULATORY MECHANISMS
neuronal NOS and COX-2 in the MD and of renin in the
afferent arterioles of FH rats preceded the development of
glomerulosclerosis (1579). Thus preglomerular vasodilation by NO, perhaps driven by a COX-2 metabolite, may
combine with hypertension caused by high ANG II to impair renal autoregulation and increase PGC that culminates
in barotrauma manifest as FSGS.
Linkage analysis showed that genetic loci on chromosome 1
of FH rats cause the hypertension, impaired autoregulation,
and proteinuria (1518 –1521). Transfer of this region from
BN into FH rats improved RBF autoregulation, normalized
the elevated PGC, and reduced protein excretion and the
progression of renal disease (922, 1610), whereas transfer
of this chromosomal region from FH rats into normotensive
controls attenuated renal autoregulation and led to FSGS
(1518). This provides strong evidence that the selective impairment of the renal myogenic response and the hypertension in this model are genetically determined and are causally related to glomerulosclerosis. The particular genes involved have yet to be identified.
Thus the selective impairment of renal myogenic responsiveness in FH rats reported in most studies despite preserved MD-TGF, PE-induced vasoconstriction, and myogenic responses in other vascular beds, suggests that the
defect in renal autoregulation is the outcome of genetically
determined changes in the preglomerular vasculature. The
weak myogenic response likely accounts for the attenuated
renal autoregulation that, in the context of hypertension,
leads to barotrauma and CKD. This conclusion is supported by recent studies of the FH hypertensive, consomic
and congenic rat strains, which demonstrate the importance
of autoregulation in preserving glomerular structure and
function.
8. BN rat
The BN rat is of special interest because it develops renal
failure despite a low BP, likely related to weak and inconsistent renal autoregulation because of excessive renal NO
generation that can prevent full vasoconstrictor responses
(260, 916). Although the BN kidney is susceptible to hypertension-induced kidney disease (260), the BN lives a long
life, perhaps due to its low BP (916). Cross-transplantation
studies demonstrated that the kidney of the normotensive
BN rat was inherently more susceptible to hypertensioninduced damage than the SHR (260, 916), thereby locating
the deficit within the kidney itself. Surprisingly, the kidneys
of BN rats have efficient steady-state RBF autoregulation
with a basal AI of 0.19 (922), but this is unusually fragile
since they are susceptible to injury with even moderate hypertension or enhanced oscillations in RPP. Dynamic admittance transfer function analysis identified an apparently
normal myogenic response with spontaneous changes in
RPP, but a weaker myogenic response to larger, forced
changes in RPP (1563). Thus incomplete autoregulation
464
could underlie the susceptibility to hypertensive renal injury. Cupples and co-workers (1569, 1570) reported that
the attenuated myogenic autoregulation was improved by
nonselective NOS inhibition or by inhibition of iNOS but
not of nNOS, implicating high NO generation from iNOS
as the cause of the blunted myogenic response. In contrast,
the renal autoregulation of normal Wistar rats was unaffected by inhibition of iNOS, but the strength of the myogenic response is enhanced by inhibition of nNOS (1358).
Since these BN rats also have exaggerated depressor response to ACh, which was normalized by global NOS inhibition, they also may have an enhanced eNOS-derived NO
(1570). Wang and Cupples (1570) concluded that the normal buffering of the myogenic response by MD nNOSderived NO was dominated in BN rats by an inappropriate
release of NO by iNOS, and perhaps by eNOS, that attenuated the renal myogenic response. The roles of NO in renal
autoregulatory mechanisms were discussed in detail earlier
in section VIC.
BN rats have a preserved myogenic response of cremaster
arteries and gracilis muscle resistance arteries that depended on 20-HETE production (445). Impaired myogenic
tone has been reported of cerebral arterioles (322) and may
contribute to their susceptibility to cerebral hemorrhage
and stroke.
Recent studies show that a 2.4-Mbp region of chromosome
1 was critical for normal RBF autoregulation since its substitution from BN into FH rats improved their RBF autoregulatory efficiency and afferent arteriolar myogenic responses, reduced BK channel activity (168), and improved
the myogenic tone of cerebral arteries (1147).
In summary, BN rats have labile renal autoregulation that
breaks down during hypertension. The weak link is identified as an impaired dynamic myogenic response related to
dysregulated overproduction of NO, but the molecular
mechanisms have not yet been defined. The defective myogenic response is considered genetically determined by sites
on chromosome 1 that may impair both renal and cerebral
vasoconstriction during increased PP.
C. CKD and RRM
A fundamental problem with human CKD is its propensity
to undergo a detrimental switch from beneficial adaptations
that restore GFR to pathological proteinuria and declining
renal function (637). This sequence is modeled by a 50 –
85% RRM that is characterized in rodents by initial increases in glomerular size, PGC, and SNGFR and hypertrophy in remnant nephrons and followed by proteinuria and
progressive tubulointerstitial fibrosis and glomerulosclerosis usually accompanied by hypertension (29, 144, 147).
The rate and the magnitude of these changes depends on the
species, age, amount of renal mass removed, and the tech-
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CARLSTRÖM ET AL.
nique (surgical ablation or infarction). The infarction
method causes ischemic, renin-dependent hypertension and
a more rapid decline of GFR, but is a less representative
model for human CKD where renal tissue is not clearly
ischemic and PRA is generally suppressed. These defects
were accelerated by high dietary intakes of protein or salt
(147, 803). Bidani and colleagues related the renal damage
to hypertension coupled with impaired autoregulation that
allowed transmission of enhanced BP fluctuations to the
glomeruli to initiate barotrauma (103, 104, 108, 112, 496,
504).
Nephron adaptations have been studied extensively after
either UNx or 5/6 Nx and generally produce similar results.
The SNGFR of Munich-Wistar rats doubles by day two of
RRM and triples by 2 wk (319, 636, 637, 1165), restoring
whole kidney GFR and RBF almost to normal (497). The
early renal vasodilatation is attributed to enhanced PG production (497, 1166, 1167). Proteinuria and mesangial expansion are apparent by 2 wk and are accompanied by an
increased glomerular volume and capillary diameter (518,
637, 1119). There is a ⬃10 mmHg increase in PGC as a
result of a preferential decrease in afferent arteriolar resistance (357, 876, 1166). Rats with RRM had persistent systemic hypertension, progressive proteinuria, and glomerular mesangial expansion and segmental sclerosis by 8 wk
(31). The decline in renal function was considered to be
secondary to an initial increase in PGC, SNGFR, and
SNGBF (29, 144, 147). Inhibition of the RAS lowered BP
and PGC and lessened the proteinuria and glomerulosclerosis in the RRM infarction rat model. This was accompanied
by a normalization of SNGBF and SNGFR by a relatively
selective reduction in the efferent arteriolar resistance (32,
1004). Impaired autoregulatory adjustments of the afferent
arteriole in rats with RRM likely contributed to the reduced
afferent arteriolar resistance despite hypertension, the increased PGC, and the glomerulosclerosis (160, 876, 1167).
The renal adaptations and impaired autoregulation are dependent on the strain and the age of the rat. Perinatal UNx
in normal rats resulted in salt-sensitive hypertension, exaggerated MD-TGF, proteinuria, increased glomerular volume, and renal injury by 3 mo (186, 1611) which were
ascribed to increased ROS and NO deficiency (181, 185).
UNx in neonatal SD rats led to renal vasodilation and complete loss of steady-state RBF autoregulation at 5– 6 wk
attributed to overproduction of PGs (235–237). However,
UNx in adult SD rats increased basal RBF but with little
impact on whole kidney RBF autoregulation (237). Weak
autoregulation in UNx FH rats accelerated the process of
progressive renal failure with increased PGC and SNGFR
evident by 12 wk, followed by severe proteinuria and a fall
in GFR (1371).
SHR kidneys have highly efficient steady-state RBF autoregulation with normal PGC, as discussed in section VIIB1
(42, 58, 358, 394, 707, 1471) and minimal glomerular
damage (358, 394, 707, 1471). After UNx, the remnant
kidney of young SHR has elevated PGC and they develop
proteinuria (93, 358, 360). However, adult SHR retained
efficient overall steady-state RBF autoregulation after UNx
(709). The renal adaptations were more severe in 5/6 Nx
rats. Within 2 wk of 5/6 Nx produced by surgical ablation
in adult SHR, hypertension worsened and RBF autoregulation was abolished with evident injury to preglomerular
arteries, arterioles, and glomeruli (107). Normal rats subjected to 5/6 Nx also developed hypertension and, by 3 wk,
had impaired steady-state RBF autoregulation (503). Their
juxtamedullary afferent arterioles became hypertrophic and
their arteriolar autoregulatory response was impaired
(903).
Hypertension and elevated PGC are considered key elements
in renal damage in UNx SHR and 5/6 Nx Munich-Wistar
rats since injury was mitigated by antihypertensive treatment with hydralazine, hydrochlorothiazide, and reserpine
(501); salt restriction (357, 876); or with ACE inhibition or
even with a CCB in some studies (360, 362). However,
impaired renal autoregulation also was a critical element in
renal damage since a low-protein diet improved steadystate RBF autoregulation and prevented proteinuria or renal damage without prominent effects on BP in 5/6 Nx rats
(112, 502). Moreover, loss of autoregulation by blockade
of VOCCs by CCBs in some other studies exacerbated renal
damage in rats with RRM despite lowering their BP (499,
500, 502, 503).
The best method to evaluate autoregulation and its mechanisms in RRM is not clear. Frequency analysis of dynamic
RBF autoregulation suggests preserved autoregulation in
rats with RRM. However, this contrasts with defective RBF
autoregulation observed in steady-state studies (109). Bidani et al. (109) concluded that the staircase steady-state
method provides a better measure of susceptibility to hypertensive glomerular damage, but the reason for the preserved
dynamic RBF autoregulation is unresolved.
Most studies have concluded that renal damage requires, or
is accelerated by, a high BP. Thus rodent strains that do not
develop hypertension after RRM, such as WKY rats (110)
or C57Bl/6 mice (861), are relatively resistant to renal damage after RRM despite impaired autoregulation and myogenic responses. However, after the induction of hypertension, WKY rats with RRM indeed sustain renal damage
(121, 609, 1282, 1451, 1452) as did C57Bl/6 mice infused
with ANG II or treated with DOCA and salt (111, 180,
1237).
Some studies have dissociated worsening autoregulation
from progression of CKD. Thus the myogenic response of
renal afferent arterioles isolated from C57Bl/6 mice was
attenuated progressively over 3 mo after RRM (861). While
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RENAL AUTOREGULATORY MECHANISMS
a high-salt diet enhanced the defects in myogenic responses,
there was no glomerulosclerosis and only mild tubulointerstitial fibrosis (861), perhaps reflecting the absence of hypertension even with a high-salt diet (861). Rho-kinase inhibition in SHR after subtotal Nx attenuated renal autoregulation but paradoxically reduced the renal damage (594).
Blockade of PG production in rats with established RRM
increased the afferent and efferent arteriolar resistances, but
did not improve renal autoregulatory efficiency or prevent
renal damage (497, 1063). ACE inhibition after RRM failed
to fully restore RBF autoregulation but was protective of kidney function (503). Anti-inflammatory agents given to rats
with RRM prevented the rises in SNGFR and PGC and the
development of proteinuria and decreased the mesangial proliferation but increased the hypertrophy of afferent arterioles
(121, 609, 1451, 1452). Blockade of ROS generation by tempol or by inhibition of xanthine oxidase protected kidneys of
rats (1282) or mice (861) with RRM without affecting BP.
Nevertheless, the weight of the data generally supports the
proposal of Bidani et al. that both hypertension and impaired
renal autoregulation are required after RRM for kidneys to
develop glomerulosclerosis. However, changes in Rho/Rho kinase, PGs, ANG II, and ROS can impact RRM progression
apparently independent of effects on autoregulation or BP.
Anti-inflammatory or antioxidant drugs might maintain renal
microvascular function after RRM (903, 1112), but this requires further study.
Impaired myogenic constriction of mesenteric arteries of
hypertensive 5/6 Nx rats was restored by long-term inhibition of ACE or antagonism of AT1 receptors that reduced
BP and renal injury (1528, 1537). Tempol plus catalase
improved myogenic constrictor response of mesenteric arteries of rats with RRM but not those with prolonged AT1
receptor blockade (1528), suggesting that ANG II-induced
ROS can impair autoregulation of nonrenal arteries. This
could provide a link between damaged kidneys that release
renin and impaired systemic microvascular function via
ROS generation.
The response to RRM has been studied most extensively in
rodents, and similar patterns are not always reported for other
species. Cats with RRM developed increased SNGFR (158)
and PGC (158, 159), hypertension, and proteinuria (9, 157).
Their remnant nephrons exhibited glomerular hypertrophy
and impaired renal autoregulation (160). Unlike rodents, the
feline renal parenchyma was quite resistant to structural damage (1598), and glomerular hyperfiltration was not exacerbated by increasing the protein intake (159, 1598) even when
studied over several years (1110 –1112). Thus the cat dissociates hemodynamics, and even hypertension, from structural
adaptations and the development of CKD.
Functional adaptations to RRM in dogs are less well characterized. The progression of CKD was accompanied by
glomerular hypertension and glomerular hypertrophy com-
466
bined with proteinuria, tubulointerstitial inflammation,
and oxidative stress (17, 965, 1326). Initially, 3/4 and 7/8
RRM led to increased SNGBF, SNGFR, and PGC (158), but
RBF autoregulation was impaired severely only in dogs
with 7/8 Nx (160). ANG II mediated the progression of
CKD in dogs with RRM since prolonged ACE inhibition
reduced PGC, proteinuria, and glomerular and tubulointerstitial lesions (1326), although it also reduced BP which
may have made a critical impact. Protein loading increased
GFR in normal dogs (420) and in 7/8 RRM dogs with
increased renal growth but failed to worsen the severity of
renal lesions (1598) as was established in rats with RRM
(87, 389). However, a low-protein diet in dogs with 11/12
RRM reduced the severity of proteinuria, glomerulosclerosis, and renal interstitial lesions (1196). Compared with
rodents, a higher degree and longer dosing of RRM are
required for dogs to develop renal damage. Thus rats with
even modest degrees of RRM have impaired renal autoregulation, with glomerular and systemic hypertension, and
develop renal injury quite rapidly. Some strains of mice
(notably the C57BL/6), like cats and dogs, are quite resistant to the detrimental effects of RRM. This raises concern
about whether the rat is a valid model for progressive CKD
in humans. The hypothesis derived from the rodent studies
that a very low protein intake would slow the loss of GFR in
patients with moderate or advanced CKD was disproved by
the results of a controlled clinical trial which also reported
that a low BP goal did not slow loss of GFR unless there was
⬎3 g daily of proteinuria (803). This was confirmed in a
trial of BP reduction in African-Americans with hypertensive nephrosclerosis where an ACE inhibitor was not clearly
superior to a ␤-adrenoceptor blocker in preventing loss of
GFR, unlike the reports in rats (147), although a CCB did
accelerate GFR loss, as in most animal models (13). Again,
these results of human studies challenge the relevance of the
rodent models, at least for a complete understanding of
human CKD progression.
The rapid and substantial increases in SNGFR that occur in
rats within 1 day after RRM indicate that MD-TGF is less
active, or reset, to accommodate the likely considerable
increase in tubular fluid delivery to the MD. Indeed, MDTGF responses were effectively abolished within 7 days of
RRM in most, but not all, rat nephrons (1372, 1373). The
immediate response of MD-TGF is less clear. One view is
that MD-TGF is reset within 2 h of UNx to higher levels of
tubular flow (1041) by vasodilator PGs (546). Another
thought is that MD-TGF is essentially normal shortly after
UNx despite the increase in SNGFR (117, 1372). Efficient
GFR autoregulation persisted in volume-expanded UNx
rats in the absence of a demonstrable MD-TGF, implicating
a strong myogenic response accounting for complete autoregulation (945). One week of administration of an AT1
receptor blocker attenuated the MD-TGF activity in shamoperated rats, but paradoxically normalized the previously
nonexistent MD-TGF response in 5/6 Nx rats (1372). Thus
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CARLSTRÖM ET AL.
there is a complex interplay of time, volume status, and
ANG II signaling after RRM that can impact MD-TGF in a
rather unpredictable manner.
Hypertensive rats with 5/6 Nx lost myogenic responses of
their mesenteric arteries, but this was preserved after prolonged inhibition of the RAS or after tempol plus catalase
(1528, 1537). Thus ANG II and ROS can impair myogenic
tone in nonrenal vessels from models of CKD in contrast to
the opposite effects in normal renal afferent arterioles (658,
660). However, cremaster and femoral arteries from rats
with RRM displayed enhanced myogenic contractions before the development of hypertension that were normalized
by ACE inhibition (1288, 1289). Human subcutaneous arteries from patients with end-stage renal disease (ESRD)
had an unchanged myogenic tone and lacked vascular remodeling (937). These different patterns of myogenic response in vessels from models of CKD remain unexplained.
In summary, rodent models of UNx or RRM generally display glomerular hypertrophy, increased SNGFR, and PGC.
A combination of systemic hypertension and attenuated
renal autoregulation generally are followed by proteinuria
and glomerulosclerosis. Initially, a vasodilator COX metabolite and NO participate in afferent arteriolar vasodilation and impair renal autoregulation while efferent arteriolar tone is maintained by ANG II, thereby contributing to
the increased PGC and SNGFR. Oxidative stress and inflammation impair renal autoregulation in chronic RRM models. The myogenic response is generally attenuated, but
there are complex, time-dependent effects on MD-TGF.
However, very different patterns of response and renal
damage have been reported between studies and between
different nonrenal vessels. These may depend on the degree,
method of RRM, the age of the animal, and especially its
species, which cautions against drawing uncompromising
conclusions concerning autoregulation in human CKD.
D. Diabetes Mellitus
Diabetic nephropathy entails a combination of albuminuria, proliferative glomerulonephritis, and glomerular and
tubulointerstitial fibrosis and is the leading cause of endstage renal disease (ESRD) (508, 1517). Patients with type 1
diabetes mellitus (DMT1, insulin deficient) and type 2 diabetes mellitus (DMT2, insulin resistant, usually complicating obesity or metabolic syndrome) begin to develop proteinuria and a decline in GFR after an interval of ⬃12–15 yr
(280, 942). Insulin lack or resistance and high blood glucose and hypertension are commonly associated with oxidative stress and can interact synergistically in the pathogenesis of diabetic nephropathy. Diabetic renal disease is
commonly initiated by an increase in GFR (termed hyperfiltration) and microalbuminuria (i.e., daily albumin excretion of 30 –300 mg), especially in those with DMT1 (149)
and hypertension (29, 30). Usually, the increase in GFR in
DMT1 exceeds that of RBF. Studies in rat and some humans reported that inhibition of the RAS reduces oxidative
stress and slows, but does not halt, the development of
albuminuria and glomerular sclerosis (28, 1121, 1619).
However, other studies have failed to disclose a renal benefit from inhibiting the RAS or lowering the BP in preventing DM (17, 113, 966, 967, 1326). However, ACE inhibitors or AT1 receptor blockers reduce proteinuria and slow
the rate of loss of GFR after the development of overt nephropathy with proteinuria ⬎3 g daily (146, 891, 1157).
Dietary Na⫹ restriction corrected increased SNGFR in a rat
study (66), but exacerbated abnormalities in humans with
early DM (1007). Thus fresh insight is required to develop
novel strategies to slow the progression of DM to ESRD.
1. DMT1
Streptozotocin (STZ) damages pancreatic beta cells and
thereby provides a model of DMT1 with insulinopenia and
hyperglycemia. As demonstrated and discussed in several
studies, there is renal vasodilation, increased PGC, and
SNGFR and glomerular enlargement (145, 189, 638, 1321,
1648). Control of hyperglycemia with insulin normalized
PGC, whereas SNGFR remained elevated (1321). RBF increased by 20 –50% by 2 wk after STZ if hyperglycemia
was restrained by insulin treatment, and this renal vasodilation depended on increased NO (88) but was diminished
by severe hyperglycemia (638). Impaired function of
VOCCs may explain the relatively selective afferent arteriolar vasodilatation and increase in PGC since the efferent
arteriole lack functional VOCCs (1487). Afferent arterioles
from STZ rats were remodeled independent of BP (1497).
Indeed, most models are normotensive.
Studies of renal autoregulation in rat models of DMT1
reported quite variable results. The plateau phase of steadystate RBF autoregulation was maintained in one study
(993), but the limit of autoregulation was shifted to a lower
RPP in many studies (307, 612, 874, 993, 1365, 1472),
independent of PGs (1472). However, other studies reported that RBF autoregulation was impaired within hours
of induction of hyperglycemia by STZ and persisted into the
established phase of DM with attenuated myogenic (588)
and MD-TGF responses (1509). Hyperglycemia itself is
considered important since it can attenuate steady-state autoregulation of RBF and GFR in normal dogs (1624).
Rat and rabbit models of DMT1 were accompanied by
severe endothelial dysfunction of isolated renal afferent arterioles and impaired NO-mediated vasodilation despite an
increased basal RBF (821, 1303, 1575). The reduced NO
availability may result from increased production of ROS
(821, 1121) by renal NADPH oxidase (55). However, these
studies on isolated vessels are at variance with reports of
increased GFR, persistent vasodilation (1472), and increased glomerular blood flow and PGC in intact kidneys, all
of which are attributed to excess NO (309). Thus the NO in
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RENAL AUTOREGULATORY MECHANISMS
question may derive elsewhere from the afferent arteriole,
likely the MD cells.
Increased proximal tubular Na⫹ reabsorption in rats with
early DMT1 via Na⫹-glucose cotransport reduces Na⫹ delivery to the MD and thus reduces the signal for MD-TGF.
An inactivated MD-TGF may contribute to an increased
SNGFR in STZ rats (1509), perhaps by exaggerated MD
generation of NO (1461, 1462, 1509). Thus hyperglycemia
in normal dogs increases their RBF and GFR when MDTGF is active but fails to do so in a nonfiltering kidney
(1624). An increased MD-TGF can occur despite increased
proximal Na⫹ reabsorption and reduced Na⫹ delivery to
the MD (1194). However, other factors must participate in
the increased SNGFR since adenosine A1 receptor-deficient
mice that lack functional MD-TGF (155, 896, 1426) retained a modest (1514), full (1276), or exaggerated increase
in GFR (392) in models with DMT1.
Some studies of frequency analysis of the RBF dynamics
revealed strong contributions to autoregulation by both the
myogenic and the MD-TGF mechanisms that were not impaired by diabetes (89, 874). However, another study reported an attenuated RBF autoregulation with weak contributions of myogenic and MD-TGF responses largely due
to excess NO (88). Diminished afferent arteriolar vasodilatation in diabetic models can occur despite maintained NO
production (1023) probably because of quenching of NO
by enhanced O2⫺ generation (1113, 1303, 1325).
The afferent arteriolar autoregulatory response in the JMN
preparation was normal in rats with STZ-induced DMT1
(993), but attenuated in the HNK preparation where it was
restored by blockade of COX or control of hyperglycemia
by insulin (588). However, insulin has no effect on myogenic constriction of normal afferent arterioles despite increasing NO and reducing vasoconstrictor responses to
ANG II and NE (590). Moreover, acute hyperglycemia in
normal rats dilated posterior cerebral arteries and diminished myogenic tone by an endothelium-dependent mechanism involving NO and a COX-derived PG (263), suggesting different regulation of renal and systemic microvessels
in DMT1. Cremaster arterioles from STZ-induced diabetic
rats initially autoregulated poorly, but eventually reverted
to a normal response (616). Thus the variability of autoregulatory responses may be a function of the degree of hyperglycemia and its effects to increase both NO and ROS, the
experimental preparation and the duration of the disease
process.
Defective L-type VOCC function could contribute to the
weakened myogenic and MD-TGF mechanisms reported in
STZ rats. Afferent arterioles of JMN had a reduced contraction to high KCl-induced membrane depolarization or to
the L-type VOCC agonist BAY K 8644 that was normalized
by reducing the glucose concentration (195). Impaired
468
VOCC function appeared to result from hyperpolarization
of the VSMC plasma membrane due to increased activity of
KATP and KIR channels during oxidative stress and hyperglycemia (665, 1484, 1485).
Galactose feeding to inhibit aldose reductase and polyol
metabolism models DMT1 with a normal insulin level and
a normal afferent arteriolar myogenic response. Thus hyperglycemia can inhibit myogenic tone independent from
insulin lack (426, 427).
Some studies have demonstrated enhanced myogenic responses in nonrenal vessels from diabetic animals. Whereas
myogenic regulation of cerebral cortical blood flow in STZinduced diabetic rats was normal in one study (1267), another reported enhanced cerebral myogenic constrictor
tone with reduced NO and activation of KATP channels
(1664). Femoral and skeletal muscle arterioles of rats with
STZ-induced diabetes had enhanced PKC activity that
phosphorylated p47phox and augmented NADPH oxidase
production of O2⫺ (1501, 1504), which increased speed and
strength by upregulation of VOCC activity (1504). However, one should be cautious in extrapolating these findings
to the kidney since there are clearly differences in the myogenic response and its mechanisms between vascular beds.
Moreover, careful assessment of BP shows it to fall with the
onset of DMT1 or DMT2 and to remain reduced for some
time in most studies.
In summary, the kidneys of rats with early DMT1 generally
are vasodilated with increased RBF and GFR attributed to
excess NO, which is impaired by diminishing hyperglycemia with insulin. In contrast, later stages of DMT1 are
associated with vasoconstriction, exaggerated ROS, and reduced NO. The available evidence does not allow a definitive conclusion as to whether RBF autoregulation and the
myogenic and MD-TGF mechanisms are normal or attenuated. Variability in results likely reflects differences in the
disease models or its progression. Attenuated myogenic or
MD-TGF components could contribute to afferent arteriolar dilation, glomerular hypertension, and increased
SNGFR which some studies have ascribed to attenuated
activity of VOCCs. Nevertheless, several studies of nonrenal vessels have demonstrated an enhanced myogenic response. Hyperglycemia and lack of insulin might exert differential effects on the renal and systemic arterioles. Thus
impaired autoregulation and vasodilation could result from
enhanced proximal tubule fluid reabsorption secondary to
activated Na⫹-glucose cotransport leading to reduced NaCl
delivery to the MD and attenuated MD-TGF. However,
increased SNGFR can occur in models lacking a MD-TGF
response. Regardless of the mechanism, a combination of a
prolonged increase in SNGFR and PGC is ominous since it
predisposes to barotrauma and nephropathy (948). Some of
the variability in reports between STZ studies likely relates
to insulin replacement and prevention of severe hyperglyce-
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CARLSTRÖM ET AL.
mia. Most studies before 2000 did not use insulin such that
animals lost weight and often suffered from prolonged glucose osmotic diuresis.
2. DMT2
Albuminuria is a marker for risk of CKD in patients with
DMT2 (316). The RAS may be a major mediator of glomerular adaptation, renal inflammation, and renal injury during established diabetic nephropathy with heavy proteinuria since inhibition of the RAS at this stage reduces albuminuria and affords some renal protection (316).
There are several rodent models of DMT2, as discussed
below. The obese Zucker diabetic fat rat (ZDF) fed a modestly enriched fat diet develops insulin resistance and hyperglycemia followed by proteinuria and glomerular injury
(272, 772, 773) related to increased SNGFR either without
(1101) or with increased PGC (1299). Renal ANG II was
elevated in ZDF rats (1440), and inhibition of RAS reduced
systemic and glomerular hypertension, albuminuria, and
renal damage (73, 73, 1100, 1299, 1299). ZDF rats have
increased GFR but, impaired GFR and RBF autoregulation
despite reduced NO production in the renal cortex and
medulla attributed to increased O2⫺ (450, 1440). They are
modestly hypertensive with a resetting of the pressure-natriuresis relation to favor Na⫹ reabsorption at a lower RPP.
Hyperglycemia and oxidative stress can activate PKC and
MAPK signaling (271, 279, 1429), which could phosphorylate Cxs. Indeed, kidneys from ZDF rats displayed increased Cx43 phosphorylation and reduced staining of
Cx37 in JGC (1441). Inhibitory peptides against Cx37 and
Cx40/Cx43, but not Cx43, attenuated RBF autoregulation
in control Zucker rats, but did not further decrement the
weak autoregulation in kidneys of ZDF rats (1441). Similar
changes in Cxs in VSMCs may contribute to abnormal
myogenic and MD-TGF responses during diabetes.
Myogenic constrictor and ACh-induced vasodilation of afferent arterioles of the HNK of ZDF rats were both blunted
but were improved by sensitization to insulin release with
troglitazone (591). Insulin buffered ANG II and NE-induced vasoconstriction in the HNK of normal rats that was
attributed to increased NO, but these effects were attenuated in ZDF rats (591), perhaps reflecting oxidative stress.
A hybrid cross of ZDF with spontaneously hypertensive
heart failure rats developed hypertension, proteinuria, and
glomerulosclerosis (495) despite efficient steady-state RBF
autoregulation (AI ⬍0.1) and dynamic transfer function
with normal myogenic and MD-TGF responses (495). Thus
factors other than impaired renal autoregulation are responsible for kidney damage in this model of DMT2.
The myogenic tone of skeletal muscle arterioles from ZDF
rats was normal initially but became enhanced in older
hypertensive animals by a ROS-dependent mechanism that
diminished NO signaling (444, 885). Cerebral arteries of
ZDF rats also had reduced vasodilation to ACh or hypoxia
and enhanced ROS-dependent myogenic constriction
(1180). Although generation of ROS in the ZDF rat may
underlie enhanced myogenic responses in nonrenal vascular
beds, it is unclear whether this occurs in the renal microcirculation.
Otsuka Long-Evans Tokushima rats develop late-onset,
non-insulin-dependent hyperglycemia, moderate obesity,
mild hypertension, and increased GFR and RBF (1506). An
impaired steady-state autoregulation of total and deep cortical blood flow and MD-TGF preceded the diabetic phase
and persisted into the established phase (584). The PGC in
glomeruli of deep versus superficial nephrons was increased
by 20 mmHg (584). This interesting model with insulin
resistance and later development of DMT2 has a weakened
MD-TGF mechanism that may underlie increased RBF and
PGC, impaired autoregulation, and subsequent renal injury.
Goto-Kakizaki rats are a lean Wistar substrain that develops early-onset DMT2 with hyperglycemia despite normal
insulin levels followed by renal and glomerular hypertrophy, glomerular basement membrane thickening, mesangial
expansion, and albuminuria (1327) despite normal BP and
reduced GFR (784, 1327). Hypertension induced by
DOCA-salt accelerated the development of proteinuria and
nephropathy (234). Thus this is a model of a lean, hyperglycemic, euinsulinemic, normotensive DMT2 with prominent renal functional and structural changes characteristic
of human diabetic nephropathy. The myogenic responses
were maintained or augmented in cerebral and mesenteric
arteries of diabetic Goto-Kakizaki rats (784, 785, 1269),
with normalization by glycemic control (784, 1269). Renal
hemodynamics and autoregulatory mechanisms have not
been characterized in this intriguing model.
The leptin receptor-deficient db⫺/db⫺ mouse model of DMT2
develops dyslipidemia, obesity, hyperglycemia, glomerular hypertrophy, and albuminuria (1355) with increased GFR while
BP is normal (888, 889). MD-TGF activity was normal (888,
889), but after correction for the depleted ECV by the osmatic
diuresis from glucosuria the SNGFR increased further and the
MD-TGF activity was abolished (889). The increase in GFR in
volume-replete db⫺/db⫺ mice was ascribed to overproduction
of NO by nNOS in the MD (889). Afferent arterioles in the
JMN preparation of db⫺/db⫺mice were dilated, but had normal autoregulation to increased RPP and normal contractions
to ANG II (1155), suggesting a normal myogenic response.
MD-TGF was normal in JMN but impaired in superficial
nephrons, which might reflect differences in A1 receptor signaling. Myogenic tone of the preglomerular vasculature in the
absence of MD-TGF has not been investigated to date.
Mixed results have been reported for nonrenal vessels from
db⫺/db⫺ mice. Myogenic tone was increased in mesenteric
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RENAL AUTOREGULATORY MECHANISMS
and coronary arteries but was normalized by inhibition of
epidermal growth factor receptor tyrosine kinase (92, 983)
and was related to activation of a vasoconstrictor prostanoid activating TP receptors and to reduce NO (858). Likewise, myogenic tone of gracilis skeletal muscle arterioles
was enhanced by a constrictor prostanoid produced by
COX-2 that activated TP receptors secondary to increased
H2O2 production (61, 382). However, other studies of coronary arteries reported preserved myogenic tone and normal TP responses (1017) despite reduced NO and increased
ROS production (62).
of MD-TGF, following enhanced proximal reabsorption, may
contribute to afferent arteriolar dilation and increased
SNGFR. Glomerular damage can be dissociated from hypertension and impaired renal autoregulation in some models,
thereby highlighting the importance of other, as yet undiscovered, mechanism of renal damage in DMT2.
3. Clinical studies of renal autoregulation in diabetes
and nephropathy
Christensen and co-workers (251–255) studied GFR from
measurements of inulin clearance in human diabetics before
and after an acute 15–20 mmHg reduction in mean BP
produced by oral clonidine (FIGURE 9). The dotted line in
FIGURE 9 indicates the GFR response without any autoregulation (AI ⫽ 1.0). Normal subjects (FIGURE 9F) had excellent autoregulation with only a 1–2% reduction in GFR
when BP was reduced by 18% (253). GFR autoregulation
In summary, studies in rodent models of hyperglycemic, insulin-resistant DMT2 have generally demonstrated renal vasodilation, increased PGC, and GFR. Renal autoregulation and
the myogenic and MD-TGF mechanisms are often normal or
modestly attenuated. Autoregulation is generally improved by
glycemic control or by an insulin-sensitizing agent. Resetting
A
DMT1 (10 yrs); no nephropathy
ΔMAP (%)
-15
-20
-10
-5
0
B
-20
0
C
DMT1 (27 yrs); no nephropathy
ΔMAP (%)
-15
-10
-5
0
-20
0
-15
-10
-5
-5
Normal blood
glucose
-10
-5
Control
ΔGFR
(%)
-15
-10
Spironolactone
-20
DMT2 (14 yrs); no nephropathy
ΔMAP (%)
-20
-15
-10
-5
0
E
0
-5
ΔGFR
(%)
-15
-10
-5
-10
-15
-15
-20
-20
DMT2 (15 yrs); with or without nephropathy
ΔMAP (%)
-20
0
Control
F
Non-diabetic nephropathy
ΔMAP (%)
-20
0
0
ΔGFR
(%)
-15
-10
-5
0
0
No nephropathy
Irsadipine
-5
Control
-5
-5
Nephropathy
-10
ΔGFR
(%)
-10
ΔGFR
(%)
Nephropathy
-10
-15
-15
-15
-20
-20
-20
FIGURE 9. Data have been redrawn from studies of autoregulation of glomerular filtration rate (GFR) during
short-term reductions in mean arterial pressure (MAP) produced by oral clonidine administration to patients
with diabetes mellitus type 1 (DMT1) or type 2 (DMT2), and/or nephropathy (broken line and open circle) and
appropriate control subjects (solid line and closed circle). Perfect autoregulation (AI ⫽ 0) is equated with no
change in GFR with MAP. An absence of autoregulation (AI ⫽ 1.0) with equal changes in GFR and MAP is
depicted by the dotted lines in each panel. A: patients with DMT1 but without nephropathy at an average of 10
yr after diagnosis. Those with high blood glucose had a similar autoregulation as those with normal blood
glucose (control) (255). B: patients with DMT1 but without nephropathy at an average of 27 yr after diagnosis.
Autoregulation was impaired in subjects with DMT1 (control), but was not altered by mineralocorticosteroid
blockade with spironolactone (1293). C: patients with DMT2 but without nephropathy at an average of 13 yr
after diagnosis. Autoregulation was mildly impaired (control), but was not affected by blockade of AT1 receptors
with cansdesartan (254). D: patients with DMT2 without nephropathy at ⬃14 yr after diagnosis. Autoregulation was quite well maintained (control), but was impaired severely by blockade of L-type VOCCs with isradipine
(251). E: patients with DMT2 at 15 yr after diagnosis. Autoregulation was quite well maintained in the group
without nephropathies (control) but was impaired in those with nephropathy (252). F: autoregulation in normal
subjects was excellent (control), but was impaired in those with nondiabetic nephropathy (253).
470
0
Control
Blood
glucose
D
DMT2 (13 yrs); no nephropathy
ΔMAP (%)
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ΔGFR
(%)
CARLSTRÖM ET AL.
also was well maintained after ⬃10 yr of DMT1, even with
poor glycemic control (FIGURE 9A) (255), but became impaired after ⬃27 yr and was not improved by reduction in
BP by a mineralocorticoid receptor blocker (FIGURE 9B)
(1293). GFR autoregulation was excellent after ⬃13 yr of
DMT2 and was not affected by AT1 receptor blockade (FIGURE 9C) (254), but was almost abolished by VOCC blockade with isradipine (FIGURE 9D) (251). GFR autoregulation
was impaired severely with DMT2 and nephropathy (FIGURE 9E) (252) and in other patients with nondiabetic nephropathy (FIGURE 9F) (253). These data demonstrate that
GFR autoregulation is well preserved in subjects with early
DMT1 or 2, but becomes quite severely impaired later in
the disease, with the development of nephropathy or after
treatment with a CCB.
VIII. CONCLUSIONS
Autoregulation relates preglomerular vascular resistance to
changes in RPP. It thereby stabilizes the RBF, PGC, and GFR
and protects glomerular capillaries from barotrauma during hypertension. Autoregulation in the normal kidney is
highly efficient. It involves a unique combination of tubular
and vascular control mechanisms (FIGURE 6). The major
mechanisms entail a rapid myogenic response and a more
delayed MD-TGF response within the JGA. In addition,
there appear to be contributions from a poorly characterized third mechanism and modulation by a CT-GF system.
Although the myogenic phenomenon was described more
than a century ago, the precise mechanisms for sensing mechanical distension and promoting the response in VSMCs
are still not fully understood. Increased [Ca2⫹]i in arteriolar
VSMCs following mechanical distension is obligate for the
initiation of the response, but prolonged, maintained vasoconstriction also entails enhanced Ca2⫹ sensitivity involving PKC, RhoA/Rho-kinase, and/or ROS signaling (FIGURE
8). Initiation can be triggered by stretch-sensitive cation
channels, integrin-cytoskeleton interactions, and/or GPCR
signaling. VSMC membrane depolarization and Ca2⫹ entry
via VOCCs are central to Ca2⫹ signaling for the myogenic
and MD-TGF-induced vasoconstrictor components of autoregulation. Impaired renal autoregulation is observed in
many, but not all, models of hypertension, diabetes, or intrinsic renal disease. Further investigations are warranted to
advance our understanding of the underlying cellular are
molecular events in these important basic regulatory mechanisms, since they likely contribute to progression of renal
damage.
ACKNOWLEDGMENTS
Address for reprint requests and other correspondence: M.
Carlström, Dept. of Physiology & Pharmacology, Karolinska Institutet, Nanna Svartz Väg 2, S-171 77, Stockholm,
Sweden (e-mail: mattias.carlstrom@ki.se).
GRANTS
The authors’ work was supported by National Heart, Lung,
and Blood Institute Grants HL68686 (to C. S. Wilcox) and
HL02334 (to W. J. Arendshorst); National Institute of Diabetes and Digestive and Kidney Diseases Grants DK036079 and DK-049870 (to C. S. Wilcox); Swedish Research Council Grant K2012-99X-21971-01-3 (to M. Carlström); Swedish Heart and Lung Foundation Grants
20110589 and 20140448 (to M. Carlström); the Swedish
Society for Medical Research (to M. Carlström); Jeanssons
Foundation Grants JS20130064 and JS2011-0212 (to M.
Carlström); the Wenner-Gren Foundation (to M. Carlström); the Swedish Society of Medicine (to M. Carlström);
Karolinska Institutet Research Foundations Grant
2014fobi41264 (to M. Carlström); the George E. Schreiner
Chair of Nephrology (to C. S. Wilcox); the Hypertension,
Kidney, and Vascular Research Center of Georgetown University (to C. S. Wilcox); the Smith Family Trust Fund (to
C. S. Wilcox); as well as the Joseph Gildenhorn/Spiesman
Family Foundation Incorporated and by Ms. Alma Gilde
(to C. S. Wilcox).
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared
by the authors.
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