Physiol Rev 90: 607– 673, 2010;
doi:10.1152/physrev.00011.2009.
Physiology of Kidney Renin
HAYO CASTROP, KLAUS HÖCHERL, ARMIN KURTZ, FRANK SCHWEDA, VLADIMIR TODOROV,
AND CHARLOTTE WAGNER
Institute of Physiology, University of Regensburg, Regensburg, Germany
I. Introduction
II. The Renin Gene
A. Regulatory noncoding sequences of the renin gene
B. Regulation of renin mRNA stability
C. Control of renin gene expression at the cellular level
D. Sites of renin expression
E. Development of renal renin expression
F. Recruitment of renin expression in the adult kidney
III. The Juxtaglomerular Cell
A. Processing and secretion of renin in juxtaglomerular cells
B. Electrical properties of juxtaglomerular cells
C. Intercellular contacts of juxtaglomerular cells
D. Intracellular signals controlling renin release
IV. Local Control of Renin Secretion
A. Tubular control of renin secretion
B. Vascular control of renin secretion
C. Neural control of renin secretion
V. Systemic Control of Renin Synthesis and Secretion
A. Blood pressure
B. Salt intake
C. Hormones, autacoids, and other mediators
V. Action of Renin
A. AT1 and AT2 receptors
B. Renin/pro-renin receptor
C. The ANG-(1–7)-ACE2-Mas axis
VII. Conclusion
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Castrop H, Höcherl K, Kurtz A, Schweda F, Todorov V, Wagner C. Physiology of Kidney Renin. Physiol Rev 90:
607– 673, 2010; doi:10.1152/physrev.00011.2009.—The protease renin is the key enzyme of the renin-angiotensinaldosterone cascade, which is relevant under both physiological and pathophysiological settings. The kidney is the
only organ capable of releasing enzymatically active renin. Although the characteristic juxtaglomerular position is
the best known site of renin generation, renin-producing cells in the kidney can vary in number and localization.
(Pro)renin gene transcription in these cells is controlled by a number of transcription factors, among which CREB
is the best characterized. Pro-renin is stored in vesicles, activated to renin, and then released upon demand. The
release of renin is under the control of the cAMP (stimulatory) and Ca2⫹ (inhibitory) signaling pathways. Meanwhile,
a great number of intrarenally generated or systemically acting factors have been identified that control the renin
secretion directly at the level of renin-producing cells, by activating either of the signaling pathways mentioned
above. The broad spectrum of biological actions of (pro)renin is mediated by receptors for (pro)renin, angiotensin
II and angiotensin-(1–7).
I. INTRODUCTION
Since its discovery 100 years ago, an impressive
quantity of information about renin has been compiled.
Notably, researchers have determined that the renin-driven
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renin-angiotensin-aldosterone system (RAAS) plays a major
role not only in the homeostatic processes, such as blood
pressure and fluid volume control, but also in the development and progression of fibrotic/hypertrophic diseases. We
have learned to distinguish between the systemic RAAS,
0031-9333/10 $18.00 Copyright © 2010 the American Physiological Society
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which is mainly controlled by the production and release
of renin from the kidneys into the circulation, and the
more locally acting renin-angiotensin systems that are
present in a variety of organs. This review predominantly
focuses on kidney renin, and it is thus a follow-up of the
milestone review published in Physiological Reviews 30
years ago (181). Since then, an influx of exciting new
information about the renin gene and its regulation, the
renin-secreting cells in the kidney and their regulation,
and the activity of the renin-angiotensin cascade has accumulated and will be considered in this review. Among
these new discoveries is the identification of the local
renin-angiotensin systems, which were recently extensively reviewed in this journal (674) and will therefore not
be the focus of the present review. Our review concentrates on the organization and transcriptional control of
the renin gene and on the nature of renin-producing cells
in the kidney. It further considers the regulation of renin
secretion on the cellular level and its control by local or
systemic factors. Finally, we consider the different biological signaling pathways and their biological effects
initiated by renin activity.
Some inbred mouse strains are unique in having two
renin genes. Mouse strains with a single renin gene possess Ren-1C, while mouse strains with two renin genes
have Ren-1D and Ren-2 (3, 228). The Ren-1 and Ren-2
genes are closely related and probably originated from a
gene duplication that occurred about three million years
ago (197, 352). The functional significance of this gene
duplication remains unknown. Ren-2 is strongly expressed in the submandibular gland (197, 229). The expression pattern of Ren-1, however, correlates best between the rat and human renin genes (214, 246). In addition, the product of Ren-2 lacks key glycosylation sites
and is consequently sorted to the constitutive secretory
pathway (163) (see sect. IIIA). Originally, it was believed
that mice with two renin genes should exhibit higher
plasma renin levels. However, in contrast to this hypothesis, mouse strains expressing Ren-2 have normal blood
pressure (76, 578). A later systematic study demonstrated
that plasma renin concentrations are actually not different between mouse strains with one or two renin genes
(309).
II. THE RENIN GENE
A. Regulatory Noncoding Sequences of the Renin
Gene
The structure of the renin gene (Ren-1) has been
determined for several different species, including sheep,
rats, humans, dogs, and mice (13, 103, 245, 313, 341, 671).
Sequence analysis has revealed high interspecies homology in the structural elements of the gene. More specifically, the mouse and rat renin genes possess nine exons
and eight introns, while the human and sheep renin genes
contain one additional exon (exon 5A) that encodes three
additional amino acids. In both humans and mice, the
renin gene was mapped to chromosome 1.
The 5⬘-flanking noncoding region plays a central role
in regulating the renin gene in all species studied. This
region is therefore considered as a classical promoter, i.e.,
a 5⬘-cis-acting regulatory element (Fig. 1). Most of the
information on the function of the renin promoter has
been obtained from cell culture models. The isolation of
the clonal renin-producing cell line As4.1 from the kidney
of simian virus 40 (SV40)-T antigen transgenic mice has
provided an important tool for studying the cell-specific
regulation of renin transcription (802a). The isolation of
FIG. 1. Structural organization of the renin promoter. Schematic map of the 5⬘-flanking regulatory elements of the renin gene and the binding
of the transcription factors. Double-headed arrows bind the conserved regulatory regions in mouse (mRen) and human (hRen) renin genes.
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the native renin-expressing juxtaglomerular (JG) cells in
primary cultures also represents a relevant model; however, it has two limitations. First, the expression of renin
is turned off within several days in the culture, and second, JG cells usually represent only a minority of the
isolated cells. These disadvantages of the primary JG cell
cultures appear to have been overcome recently by a
double-transgenic labeling of cells of renin lineage in vivo
and their subsequent isolation and cultivation in vitro
(681). However, this model is still awaiting a broader
application to confirm its efficiency and reliability.
The function of renin gene regulatory sequences
in vivo has been intensively studied during the last few
years. Recently, a number of transgenic mice with various
deletions in the renin promoter have been generated.
Surprisingly, some in vivo results have deviated from the
models predicted on the basis of the existing cell culture
data (269a, 857, 989, 990). Some of these discrepancies
may reflect species-specific differences; however, it also
appears possible that the in vitro findings may not be
completely relevant for the in vivo situation. In any case,
there is still a great number of cell culture data on the
function of the renin promoter that needs to be validated
at the level of the whole organism. Therefore, in the
following sections, which concern the molecular and cellular mechanisms of renin gene expression (sect. II, A–C),
we have focused on the results from cells with endogenous renin production, followed by discussion of the in
vivo data if available.
1. The proximal renin promoter
A 123-bp sequence from ⫺117 to ⫹6 in the mouse
Ren-1C gene (all positions hereafter are relative to the
transcription starting site) was originally defined as a
“proximal renin promoter” (690). This sequence was
found to be necessary for the maximal cell-specific expression of mouse and human renin genes (83, 690). The
proximal promoter is highly homologous in human,
mouse, and rat renin genes and contains a perfectly conserved TATA box. Further upstream, the homology is
interrupted by an ⬃500-bp insertion that is only present in
mouse renin genes (106). Currently, the term proximal
renin promoter refers to the 5⬘-regulatory sequences located roughly downstream to position ⫺200, since a row
of important cis-regulatory elements has subsequently
been identified in this region.
The general transcription factor binding site pattern
of the proximal renin promoter suggests that this region is
important for the basal activity of the renin gene, for the
transcriptional regulation by cAMP and nuclear receptors
and for the control of renin gene expression during ontogenesis.
A) PROXIMAL PROMOTER CIS-ACTING ELEMENTS TARGETED BY
CAMP. Renin is a cAMP-inducible gene. The presence of a
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functional cAMP response element (CRE) is a characteristic feature of the renin promoter in all species tested
(83, 264, 442, 620, 663, 794, 975). A proximal CRE sequence is located at ⫺226 to ⫺219 in the human renin
gene (975). However, only the 3⬘ half of this motif is
evolutionarily conserved, which makes its role in the
regulation of the renin gene uncertain. There is substantial evidence suggesting that several CRE-unrelated proximal promoter sequences are also involved in the cAMPdependent regulation of the renin gene. A Pit-1 transcription factor binding site at ⫺77 to ⫺67 in the human renin
promoter is necessary for stimulation of renin transcription by cAMP (265, 833, 834). The homologous sequence
in the mouse Ren-1C gene, which spans ⫺72 to ⫺50, was
also shown to be important for transcriptional activity.
This DNA motif is bound by the homeodomain proteins
HOX and PBX (135, 665, 669). The HOX/PBX core binding
sequence was recently found to be indispensable for the
basal renin expression level in the kidney in vivo (269a,
857).
Interestingly, the very same sequence is targeted by
the retinoblastoma gene product (RB) to stimulate the
Ren-1C promoter activity in human embryonic cells,
which do not however express endogenous renin (852).
Therefore, the role of RB in the cell-specific control of
renin transcription remains to be further elucidated. The
nuclear receptor LXR-␣ also mediates the cAMP effect via
a motif called CNRE (cAMP and negative regulatory elements). The CNRE is located at position ⫺128 to ⫺115 in
the human renin gene and at ⫺611 to ⫺599 in the mouse
Ren-1D gene (356, 357, 850, 851). This sequence displays
little homology to either the CRE or the classical DR4
LXR-responsive element (DR4/LXRE). However, the partial deletion of the proximal promoter LXR-␣ binding
motif affected neither the basal expression nor the regulation of the renin gene in vivo, thus contradicting the
physiological significance of the CNRE (see also sect.
IIC1) (857).
B) FURTHER CIS-ACTING ELEMENTS IN THE PROXIMAL RENIN
PROMOTER. The human renin gene was recently identified as
the first gene regulated by the transcription factor peroxisome proliferator-activated receptor-␥ (PPAR-␥), which
occurs through a nontypical Pal3 (palindrome with a 3-bp
spacer) binding site located at ⫺148 to ⫺134 (881). Although the renin Pal3 site resides in an evolutionarily
conserved promoter region, we found that mouse and rat
renin Pal3 elements are transcriptionally silent (882). The
critical bases of the Pal3 motif that confer full inducibility
by PPAR-␥ were mapped to the 5⬘-repeat and to the last
base of the spacer (882). The human renin Pal3 sequence
is unique in selectively binding PPAR-␥, which permits the
maximal agonist-dependent stimulation of transcription,
particularly at low cellular levels of PPAR-␥. Thus the
human renin gene appears to be more sensitive to PPAR-␥
than its murine orthologs.
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The nuclear effector of the Notch signaling pathway
(CBF1) bound to a sequence in the proximal promoter
(⫺210 to ⫺191, ⫺679 to ⫺660, and ⫺185 to ⫺166 in
human, mouse, and rat renin genes, respectively) was
recently identified to be a partner of the HOX/PBX transcription factors (665, 669). Both the Notch system and
the HOX proteins are important during embryonic development; more specifically, they are believed to participate
in regulating the tissue-specific expression of the renin
gene (494, 559, 665). In addition, the developmentally
active Ets transcription factors have also been reported to
interact with sequences within the proximal renin promoter (665).
Another important regulatory sequence lies within
the proximal promoter of the mouse Ren-1C gene, just
upstream of the HOX/PBX-binding site (667). The deletion
of this DNA-fragment (⫺197 to ⫺70) resulted in an almost
complete loss of renin transcriptional activity. At least
two transcription factor families, namely, NFI and Sp1/
Sp3, bind to this region of the proximal promoter (667).
2. Renin gene enhancers
In addition to the proximal promoter region, the
renin gene is controlled by two known 5⬘-flanking enhancer elements. An enhancer is typically defined as a
regulatory DNA sequence that strongly induces transcription in an orientation and position-independent manner.
A) RENAL ENHANCER. A 242-bp enhancer element was
identified at ⫺2866 to ⫺2625 in the mouse Ren-1C gene.
This sequence was shown to stimulate renin transcriptional activity up to 100-fold in the renin-producing cell
line As4.1 (690). Since the As4.1 cells are of renal origin,
the Ren-1C enhancer is called the “renal” or “kidney”
enhancer (690, 802a). Emerging evidence suggests that
the mouse renal enhancer directs the on/off switching
rather than the transactivation rate of the renin gene in
the single cell in vitro (601). Such a variegation model of
renin expression control is feasible because the reninproducing cells are “recruited” during chronic stimulation
in vivo (see sect. IIF). However, additional studies are
necessary to confirm or reject this concept.
The renal enhancer is also present in the human renin
promoter, although at a more distal position (about ⫺12
kb) (966). The human and mouse kidney enhancers are
highly homologous in their 202-bp distal portions, while
the similarity in their 40-bp proximal fragments (m40) is
only 45% (794). The heterology in the m40 sequence explains the lower transactivating capacity of the human
enhancer compared with the mouse enhancer (379; see
below).
The role of the renal enhancer in the regulation of
renin expression in vivo is still not completely understood. Studies of transgenic mice expressing human renin
from an artificial chromosome have demonstrated that
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the renal enhancer of the human renin gene is dispensable
for the stimulation of renin gene expression by angiotensin converting enzyme (ACE) inhibition (989). In contrast,
deletion of the renal enhancer of the endogenous renin
gene in mice has revealed that it is necessary for the full
activation of renin transcription by the combination of a
low-salt diet and the ACE inhibitor (7, 562). On the other
hand, both the human and mouse renal enhancers appear
to be critical for the basal transcription of renin, both
in vitro and in vivo (7, 989).
B) CIS-ACTING ELEMENTS IN THE RENAL ENHANCER. The downstream enhancer portion of the renin gene contains a CRE
and a more proximal E-box, which bind the CREB/CREM
and USF1/USF2 transcription factors, respectively (442,
663). These binding sites are critical for the function of
the renal enhancer, since a mutation of either one results
in an almost complete loss of its activity in As4.1 cells
(663). Moreover, CRE mediates the stimulatory effect of
the cAMP/PKA cascade on renin expression. Thus cAMP
signaling has at least two targets in the renin gene regulatory sequences, the nonconsensus CNRE site located in
the proximal promoter (see above), and a canonical CRE
located in the renal enhancer. It is still not understood
whether the distinct cAMP-targeted cis-acting elements
are redundant, thus underscoring the role of cAMP in the
transcriptional control of the renin gene, or whether each
has specific functions.
Two directly repeated TGACCT sequences are located downstream and adjacent to the E-box (379, 796).
This hexamer repeat represents the DNA binding site for
the superfamily of nuclear receptors and is generally
known as the hormone responsive element (HRE) (29).
Consistently, the nuclear receptors retinoic acid receptor/
retinoid X receptor (RAR/RXR), PPAR-␥, and the orphan
receptor Ear2 were found to bind to this enhancer element (521, 796, 882). It is important to note that the
human renin HRE differs from the mouse sequence both
in the spacer between the hexamer repeats and in the
proximal hexamer repeat (794). While the deviations in
the spacer are not critical for the transcriptional activity
of the enhancer, the substitution from A to G in the
proximal hexamer of the HRE is responsible for the lower
transactivating capacity of the human kidney renin enhancer (379). In the mouse renin kidney enhancer, the
downstream TGACCT motif is overlapped by an NF-Y
transcription factor binding site (794, 795). It has been
suggested that NF-Y prevents the binding of transcriptional regulators to the hexamer motif, thus inhibiting the
enhancer’s activity (795).
There are at least seven important transcription factor binding sites in the more distal enhancer fragment.
One of these motifs binds the Wilms’ tumor suppressor,
WT1, which inhibits renin transcription (826). The other
six motifs are bound by the NFI and Sp1/Sp3 transcriptional regulators (664). Notably, the same transcription
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factors bind to the proximal renin promoter (667). It
remains to be clarified whether these multiple renin promoter binding sites are redundant or have different functions. The mutation of either the enhancer or the proximal
NFI/Sp1/Sp3 binding sequences almost completely eliminates the renin promoter activity, thus indicating a crucial
role for these transcription factors in the control of renin
gene expression (664, 667).
C) CHORIONIC ENHANCER. A second enhancer was identified in the human renin 5⬘-flanking region between ⫺5777
and ⫺5552 (263). This enhancer delivered an ⬃60-fold
induction of the human renin promoter activity in chorionic cells and, therefore, is known as the “chorionic”
enhancer (263). However, the chorionic enhancer is not
evolutionarily conserved and was consequently found to
be transcriptionally silent in transgenic mice (990).
3. Intron I regulatory sequences
In addition to the promoter sequences, regulatory
DNA elements have been identified in intron I of the
human and rat renin genes (262, 919). Intron I has been
shown to exert a silencing effect on the renin gene expression. Closer characterization of the rat intronic silencer sequence in vitro has led to the identification of
two positive and five distinct negative cis-acting elements
(918).
B. Regulation of Renin mRNA Stability
In addition to the tight transcriptional control described above, renin gene expression is also regulated at
the posttranscriptional level (147, 499, 809). In general,
the mechanisms that stabilize or degrade mRNAs are not
completely understood. For renin mRNA, it is known that
its stability is controlled by mRNA binding proteins,
which interact with the 196-bp-long 3⬘-untranslated region
(UTR) of renin mRNA. Multiple mRNA binding proteins
have been shown to bind to the renin mRNA 3⬘-UTR (6,
811). HuR, CP1/hnRNP E1 [poly(C)-binding protein-1],
nucleolin, dynamin, and YB-1 are thought to stabilize
renin mRNA. The HADHB [hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase (trifunctional protein)-␤-subunit] protein is believed to destabilize renin mRNA, while the effects of the MINThomologous protein and the hnRNP K protein on renin
mRNA stability are unknown. Thus, in addition to the
transcriptional mechanisms, posttranscriptional modifications of renin mRNA are also important for the control
of renin gene expression. However, it is currently difficult
to evaluate to what quantitative extent each of these two
mechanisms contribute to the regulation of renin mRNA
abundance. In fact, the single cell produces more transcripts than the accumulated RNA steady-state level, demonstrating the existence of constitutive RNA degradation
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mechanisms (reviewed recently in Ref. 358). Therefore, it
has been proposed that changes in the mRNA stability
provide a faster response of renin gene expression to
regulatory signals (602).
C. Control of Renin Gene Expression at the
Cellular Level
Altogether, our knowledge of the intracellular mechanisms that regulate renin transcription suggests that the
cAMP/PKA/CREB and calcium/PKC cascades are employed by physiological cues, whereas STATs, NF␬B, and
members of the nuclear receptor superfamily probably
only become relevant in pathological situations. Similar to
the renin gene regulatory sequences, most of the information on the cellular control of renin transcription comes
from cell culture models. Consequently, not much is
known about the relevance of the in vitro identified molecular mechanisms for the regulation of renin gene expression in the whole organism. Therefore, transgenic
animals with selective and cell-specific gene inactivation
are expected to deliver novel information on this issue.
1. cAMP and protein kinase A
The second messenger cAMP is produced by adenylyl cyclases, which in turn are regulated by extracellular
stimuli through G protein-coupled receptors. cAMP exerts
its effects on transcription by activating protein kinase A
(PKA) (497). cAMP binds to the two regulatory subunits
of PKA to release two catalytic subunits from the inactive
PKA tetramer complex. The free catalytic subunits (referred to as activated PKA) translocate to the nucleus and
phosphorylate transcription factors of the cAMP response
element binding protein/activating transcription factor
(CREB/ATF) family. These transcription factors are constitutively bound to CRE in the regulatory sequences of
cAMP-driven genes and are transactivated by the PKAinduced phosphorylation (596). cAMP signaling is believed to be the central stimulatory pathway in renin gene
transcription (442, 663). cAMP mediates the stimulation
of renin expression by catecholamines/sympathetic activation and prostaglandins (146, 401, 473). In addition, the
cAMP/PKA cascade essentially determines the basal transcription rate of the renin gene (663). CREB is a prototypical representative of the CREB/ATF transcription factor family that mediates cAMP signaling to the renin gene
(265, 442, 497, 663, 975). CREB was found to bind to the
renin CRE sequences identified in the proximal promoter
and in the kidney enhancer. CREM (cAMP response element modulator) and possibly ATF1, which are close
relatives of CREB, also interact with the CRE enhancer
(442, 663). Notably, all three of these proteins share the
conserved target sequence for PKA.
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Studies in transgenic animals have unambiguously
confirmed the central role of cAMP in the physiological
control of basal renin gene expression. Chen et al. (146)
generated a transgenic mouse line with a specific deletion
of the Gs␣ protein in renin-producing cells (146). Gs␣ is an
essential subunit of the stimulatory G protein that couples
adenylyl cyclase with activating receptors such as the IP,
EP4, and the ␤-adrenergic receptors. These receptors, in
turn, mediate the effects of prostacyclin, prostaglandin
E2, and catecholamines on renin expression (241, 423).
The local knockout of Gs␣ in renin-producing cells has
been shown to sharply diminish renal renin mRNA levels
and plasma renin concentrations (PRC) (146). Unfortunately, the G protein receptor agonist-induced stimulation
of renin gene expression was not tested in the JG-specific
Gs␣ knockout mice. Thus the role of cAMP signaling in
the physiological regulation of renin transcription in vivo
remains to be definitely confirmed.
The binding of the nuclear factor LXR-␣ as a monomer to the CNRE proximal promoter motif was also reported to mediate the cAMP-dependent stimulation of
renin transcription (356, 357, 850, 851). PKA has been
suggested to phosphorylate LXR-␣ at two potential sites
within its ligand binding domain (LBD) (426). Additionally, the COOH-terminal AF-2 transactivation domain in
the LXR-␣ molecule was found to be necessary for responsiveness to cAMP (850). The renin gene in LXR-␣
⫺/⫺ mice is insensitive to adrenergic stimulation (599);
however, the CNRE sequence is dispensable for the regulation of renin expression in vivo (857). Therefore, the
mechanisms of regulation of renin transcription by LXR-␣
need to be further investigated.
cAMP also increases the stability of renin mRNA in
cultured cells (see sect. IIB) (147, 499, 811). In support of
this observation, the adenylyl cyclase activator forskolin
increased binding of the stabilizing factors HuR and CP1
to the 3⬘-UTR of human renin mRNA (6).
2. Calcium and protein kinase C
In contrast to the stimulatory function of cAMP, cytosolic calcium and/or protein kinase C (PKC) are involved in the suppression of renin expression (188, 606).
This unusual role for calcium/PKC is termed the “calcium
paradox” of renin production. Hormones such as angiotensin (ANG) II and endothelins inhibit renin gene expression and secretion by increasing the cytosolic calcium
and/or activation of PKC (293, 485, 606, 727, 728). However, the mechanism by which calcium and/or PKC inhibits renin synthesis remains, to a large extent, unknown.
Calcium was recently found to inhibit the transcription of
the human renin gene by interacting with a calcium response element in the promoter region (243). ANG II
targets the proximal 2.8 kb (606), while endothelin-1 targets the enhancer element of the mouse Ren-1C promoter
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(737). In addition, like cAMP, calcium influences renin
mRNA stability (see sect. IIB). The RNA-binding protein
dynamin has been suggested to destabilize renin mRNA in
response to increased intracellular calcium (443).
3. STAT and NF␬B transcription factors
Inflammatory cytokines, such as interleukin-1␤ (IL1␤) and tumor necrosis factor-␣ (TNF-␣), were found to
be potent inhibitors of renin production (52, 399, 668).
Cytokines appear to be relevant as factors that regulate
the renin expression during acute or chronic inflammation. The cardiovascular response to inflammation includes severe hypotension or septic shock (when hypotension is accompanied by organ failure), resulting from
the dysregulation of vasoconstrictor and vasodilator systems, whereby the activity of the latter becomes dominant
(92–94, 345). Since renin is the limiting factor for the
generation of ANG II, which, in turn, is a potent systemic
vasoconstrictor, it has been proposed that the cytokinemediated inhibition of renin expression is an important
mechanism in the pathogenesis of hypotension/septic
shock upon inflammation (52, 691). Accordingly, mice
treated with bacterial lipopolysaccharide (LPS) in an
acute model of sepsis express significantly less renin
mRNA in the kidneys, compared with their controls (52).
Neither cAMP nor the calcium signaling pathways
are currently known to be involved in the intracellular
mechanism of action of the cytokines on renin gene expression. At least two transcription factors have been
reported to mediate the suppression of renin transcription by cytokines in cultured renin-producing cells.
A) STATS. STAT (signal transducers and activators of
transcription) transcription factors play key roles in interferon- and hematopoietic growth factor-dependent
stimulation of transcription (179, 947). The inflammatory
cytokine oncostatin M was first found to suppress renin
transcription through STAT5 (52). More recently, the cytokines IL-1␤ and interleukin-6 were demonstrated to inhibit renin promoter activity via the extracellular signalregulated kinases (ERKs) and STAT3 (522, 668).
B) NF␬B. We found that the transcription factor
NF␬B is involved in the inhibition of renin gene expression through the cytokine TNF-␣ (880, 883, 884). NF␬B
interacts with CRE in the renal enhancer without directly
binding to the DNA. TNF-␣ employs at least two mechanisms to suppress renin gene expression. TNF-␣ inhibits
the transactivating capacity of the NF␬B-p65 subunit
and attenuates the binding of CREB to the CRE motif of
the renal enhancer. The latter mode of trans-inhibition
is particularly interesting because it could represent
one of the underlying enhancer-dependent mechanisms
for switching on/off the transcription, according to the
variegation model of regulation of the renin gene. Moreover, a similar mechanism is utilized by the vitamin D3
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receptor (see sect. IIC4) to suppress the renin transcription.
4. Nuclear receptors
Vitamin A (retinoic acid) has been found to increase
renin mRNA levels in vivo (796). The molecular basis for
the effect of vitamin A on the renin gene expression is the
presence of a HRE sequence that is generally targeted by
the nuclear receptors in the renal renin enhancer (29).
The retinoic acid receptor-␣ and the RXR-␣ were identified as members of the protein complex bound to the
renin enhancer HRE, and treatment with retinoic acid
stimulated renin promoter activity in an enhancer-dependent manner (796). RXR-␣ also binds to a proximal cisacting element in the human renin promoter (⫺148 to
⫺134), known as Pal3 (881). Although the role of this
motif in the regulation of renin gene expression by vitamin A is still unknown, Pal3 was found to be targeted by
another member of the nuclear receptor superfamily,
PPAR-␥ (881). Interestingly, PPAR-␥ stimulates human
renin transcription through the proximal promoter Pal3
sequence, while the human renin enhancer HRE seems to
be dispensable for this effect (881). PPAR-␥ most likely
targets murine renin genes through the HRE enhancer
sequence. Together with their different protein-binding
properties (881; see also sect. IIA, 1 and 2), the PPAR␥targeted sites of the renin gene (HRE and Pal3) are important examples for the single transcription factorbinding nonredundant cis-acting elements, which may
mediate species-specific regulation. Therefore, we are
currently generating several transgenic mouse strains to
study the mechanisms of the PPAR␥-driven renin transcription in vivo.
Unexpectedly, the vitamin D3 receptor (VDR) does
not interact with the renin HRE enhancer site. Instead, the
ligand-activated VDR represses the renin transcription by
heterodimerizing with CREB and preventing it from binding to the renin enhancer CRE (980). Vitamin D3 is considered to be a (patho)physiologically relevant inhibitor
of renin gene expression (516, 980). Accordingly, VDRdeficient mice have increased renin production, which
has led to increased water intake, hypertension, and cardiac hypertrophy (516).
D. Sites of Renin Expression
It is generally accepted that the active renin found in
the circulation of mammals almost exclusively originates
from the kidneys. However, significant amounts of plasma
(pro)renin are produced in the submandibular salivary
gland of some mouse strains. As previously mentioned,
these mouse strains possess two renin genes, of which
Ren-2 is highly expressed in the salivary glands (3, 197,
229). This renin gene duplication is specific to the mouse,
Physiol Rev • VOL
613
and its functional significance remains unknown. Notably,
even in nephrectomized and sialectomized animals, substantial pro-renin levels can be measured (405), and the
origin of the residual pro-renin remains unclear.
In addition to systemic renin, there are a number of
extrarenal tissues that express renin as a part of the local
or tissue-specific RAASs. In these tissues, renin is expressed at a much lower level than in the kidney; its
effects are therefore believed to be auto- and/or paracrine
(293). Renin is also produced locally in organs that exhibit
a blood-tissue barrier, such as the brain or the testes (190,
208, 214, 255, 670). In these organs, the local renin operates independently of the systemic RAAS. On the other
hand, in organs such as the heart and the large arterial
vessels, significant amounts of renin are taken up from
the plasma to support the paracrine activity of the locally
produced enzyme (627, 685).
Within the kidney, renin is predominantly produced
by the JG cells. Interestingly, renin is, to a lesser extent,
also synthesized in the renal proximal tubule, connecting
tubule and collecting duct, and it is believed to be involved in the local regulation of salt reabsorption and
cellular proliferation by ANG II (448, 858, 860). In particular, the expression and regulation of (pro)renin in the
connecting tubule and collecting duct have attracted attention over the last few years (729). Renin expression in
this localization may be important under conditions of
high ANG II states like diabetes (417, 688) and renovascular hypertension (702).
Renin mRNA was detected in the organs of the gastrointestinal tract, the immune system, and the female
reproductive system, as well as in the adrenal gland,
adipose tissue, eye, and skin (214, 229, 246, 270, 383, 420,
433, 735, 803, 842, 929). The local effects of tissue renin
are cell and tissue specific. These local RAASs were recently assessed in several excellent reviews (448, 512,
674).
E. Development of Renal Renin Expression
During nephrogenesis, renin expression changes in a
uniform manner in mammals (115, 200, 204, 272, 273, 275,
457, 458, 584, 694, 803), as recently illustrated in a detailed
three-dimensional view of renin expression during the
development of mouse kidneys (756). Renin first appears
in the undifferentiated metanephric blastema of embryonic kidneys (789) before vessel formation has begun,
suggesting that renin cells originate within the metanephric kidney from renin progenitor cells rather than from an
extrarenal source. Once vascularization of the kidney has
begun (around embryonic day 14 in mice and rats), reninproducing cells are exclusively distributed along the walls
of the arteriolar vessels (133, 584, 726). Renin in association with the vasculature is first present on day 15 of
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embryonic development, as it begins to be expressed in
distinct cells scattered throughout the distal part of the
evolving vascular tree. From this initial expression site,
renin begins to expand bidirectionally into larger renal
vessels, in which renin expression is not continuous and
does not resolve into a clearly predictable expression
pattern. As nephrogenesis proceeds, the arterial tree continues to mature, and the expression of renin shifts from
larger vessels to newly developed afferent arterioles. Subsequently, the renin completely disappears from the
larger vessels, becomes more and more restricted to the
afferent arterioles, and is finally localized at the classic
juxtaglomerular position. Recent data suggest that the
acquisition and maintenance of the renin cell identity is
mediated by cAMP and histone acetylation at the CRE of
the renin gene (681). The embryonic cells expressing
renin can also give rise to other cell types, and as a
consequence, inhibition of the development of renin-producing cells leads to developmental defects of the whole
kidney (682). Interestingly, cells that have switched off
renin expression during kidney development can be reactivated to produce renin in adult life (788) (see sect. IIF).
Among the afferent arterioles, renin expression is first
observed in the afferent arterioles of the juxtamedullary
zone of the kidney, and it later increasingly appears in the
midcortical and finally in the cortical zones (Fig. 2).
The functional relevance of this characteristic shift in
renin expression during metanephrogenesis is not entirely clear. It has been speculated that renin-producing
cells might guide the development of intrarenal blood
vessels, since in rat kidneys the development of a new
arterial branch is preceded by the appearance of renin
expression at the point of branching (720). In contrast,
presumptive bifurcations of the developing arteries in the
mouse kidney are free of renin, while robust expression is
detected at the mature branch points. The absence of
renin in the branching arterial tips, as well as intense
expression in the more established vessels, also suggests
that renin expression is not a prerequisite for the formation of the vascular tree in the mouse kidney (756, 844).
The cellular mechanisms responsible for the characteristic developmental changes in intrarenal renin expression are not well understood. One may assume that the
spatiotemporal appearance of direct regulators of renin
gene expression may coincide with the initiation or termination of renin expression during nephrogenesis. Some
studies have shown that the distribution of intrarenal
renin expression parallels the development of sympathetic innervation of the kidney (703), which reflects the
centrifugal pattern of renin expression and renal vasculature. In addition, the expression of the transforming
growth factor (TGF)-␤ type II receptor shifts in a manner
similar to that of renin during renal development (520),
suggesting that TGF-␤ might also be involved in triggering
developmental renin expression. The evidence for a disPhysiol Rev • VOL
FIG. 2. Renin during embryonic kidney development. Reconstruction of the ␣-smooth muscle actin immunoreactive structures (red) and
of the renin immunoreactive areas (green) in the developing mouse
kidney. The distribution of renin is shown in whole organ reconstructions (A–C) and in developing branches of arcuate arteries (D–F) on
embryonic day 16 (A and C), postpartal day 1 (B and E), and in the adult
kidney (C and F). The light green color indicates glomeruli.
tinct role of cell-to-cell communication via gap junctions
in the distribution of renin-producing cells has recently
been obtained. Renin-producing cells at all developmental
stages express the gap junction protein connexin40 (492).
Mice lacking connexin40 display a normal pattern of renin
expression in the larger vessels, but they are unable to
maintain renin-producing cells in the afferent arterioles
(493). Instead, renin-producing cells in the mature kidneys are located outside the vessel walls in the periglomerular interstitium.
The proper regulation of developmental renin expression requires switching on and off the relevant transcription factors. It has been reported that the putative
mRNA splicing protein Zis may be of relevance for the
development of renin-expressing cells (419). However, its
mode of action in renin-producing cells has not yet been
elucidated in detail. The renin gene promoter contains
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consensus binding motifs for many transcription factors
(see sect. IIA), two of which might be considered favorite
candidates. One is the Hox transcription factor, generally
known to be relevant for development, while the second
is the CRE factor, CREB (663). The deletion of both Hox
binding motifs (665, 666, 669) and CRE sites (7, 146, 442,
666, 853) has been shown to strongly reduce the basal
renin promoter activity and to blunt its stimulation
in vitro. Preliminary evidence suggests that the interruption of the cAMP pathway in vivo can nearly prevent renin
expression during kidney development (624).
F. Recruitment of Renin Expression in the Adult
Kidney
usual, as calcium inhibits rather than facilitates renin
secretion.
A. Processing and Secretion of Renin in
Juxtaglomerular Cells
Renin shares the functions both of a hormone and of
a protease. Therefore, on one hand, renin is intracellularly
processed and glycosylated like a typical secretory protein. On the other hand, it is intracellularly processed and
packed into vesicles like a typical lysosomal protein,
which finally undergoes regulated secretion.
1. Renin secretory vesicles
Plasma renin is produced and secreted by the renal
JG cells (see sect. III). These epithelial-like cells are located in the wall of the afferent arteriole in close vicinity
to the glomerulus (293). JG cells comprise a very small
cell population in the kidney. Notably, the number of
renin-producing cells in the afferent arteriole is variable,
such that chronic stimulation of renin synthesis increases
their number, and vice versa. These changes in the number of renin-producing cells are based on the unique
ability of the smooth muscle(-like) cells of the afferent
arteriole to acquire a secretory phenotype via a reversible
metaplastic transformation. Thus, in states of increased
renin production such as during impaired renal perfusion,
salt depletion, or inhibition of ANG II formation, the
larger portions of the afferent arteriole proximal to the JG
region become renin-positive (114, 146, 788). The cellular
mechanisms underlying the recruitment of renin-producing cells in the vessel walls of adult kidneys are not well
understood. It was suggested that vascular smooth muscle cells may switch into renin producers, and vice versa,
by a metaplastic transformation (114). An elegant study
has recently provided evidence that not all smooth
musclelike cells in the renal vasculature can undergo such
a switch and that the cells that can do so are genetically
programmed (788).
III. THE JUXTAGLOMERULAR CELL
Several aspects render the renin-producing JG cells
somewhat mysterious. The first aspect is the yet unexplained special position of the cells in the media layer of
afferent arterioles at the entrance into the glomerular
capillary network. The second unusual feature is the
cuboid, epithelial-like form, which coined the term juxtaglomerular epithelioid (JGE) cells. Third, the cells contain
numerous, sometimes large, dense-core secretory vesicles, but they very rarely show signs of exocytotic events.
Finally, the regulation of secretion appears rather unPhysiol Rev • VOL
615
Renin is initially synthesized as a pre-pro-renin protein. After cleavage of the presequence, the pro-renin is
directed to the cis-Golgi cisternae. From there, pro-renin
can be immediately secreted by the constitutive pathway
or sorted to the dense-core secretory granules for regulated exocytosis (Fig. 3). The correct sorting of the prorenin to the regulated secretory pathway depends on the
presence of a paired basic amino acid site in the pro-renin
molecule, which serves as a protease processing site for
granule-attached prohormone convertases (85). In addition, a decrease in the pH of the early renin granules may
facilitate the aggregation of the granule core. Accordingly,
the protogranules often contain paracrystalline cores
(862). In mice with two renin genes (Ren-1D and Ren-2),
the deletion of Ren-1D, but not Ren-2, is associated with
a complete absence of the dense-core secretory granules
in JG cells (163, 607), suggesting that the ability to form
the dense-core secretory vesicles depends on the structural characteristics of the Ren-1 protein. These characteristics may be related to the glycosylation of the protein
because renin originating from the Ren-1D gene has three
N-linked glycosylation sites, while the Ren-2-derived renin has none. Renin glycosylation may be necessary not
only for renin trafficking to the dense-core secretory vesicles (607), but also for the mannose-6-phosphate receptor-mediated uptake of renin or pro-renin in other tissues,
such as the heart (685, 900).
In addition to pro-renin, the protogranules contain
proteases such as prohormone convertases (85, 95) and
cathepsin B (579, 625), which can cleave off the 43-amino
acid NH2-terminal prosegment. These proteases require
an acidic pH for optimal activity. The autoactivation of
the proteases from their own pro-forms also depends on
a low pH of 4 – 6. The low pH of renin secretory vesicles
allows them to be stained with fluorescent dyes like quinacrine (17, 122, 687). Quinacrine staining of renin-containing vesicles has been used for dynamic visualization of
live cells to trace the exocytosis of renin-containing vesicles (687).
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FIG. 3. Subcellular structure of juxtaglomerular (JG) cells. Electron photomicrograph of a renin-producing JG cell in a mouse kidney.
A: overview of the cell. B: high-power magnification of the renin storage
organelles. RER, rough endoplasmic reticulum.
Even in renal juxtaglomerular cells in situ, only 25%
of synthesized renin is directed to the dense-core secretory granules, while 75% is constitutively secreted as prorenin (699). This source, together with the pro-renin originating from extrarenal sources, accounts for the observation that the proform accounts for 80 –90% of the total
renin in human circulation (824). The interaction of circulating pro-renin with tissue renin receptors may lead to
proteolytic or nonproteolytic activation, as well as local
generation of angiotensin and the activation of second
messenger pathways (see sect. VIB).
The release of pro-renin via the constitutive pathway
depends on the activity of the renin synthetic pathway,
i.e., the level of gene activation and transcription efficiency in the individual cell, as well as the total number of
renin-producing cells. Therefore, the acute stimulation
of renin release leads to an increase in the exocytosis
of mature renin secretory granules that contain active
renin only, whereas the chronic stimulation of the renin
system increases circulating levels of both pro-renin
and renin (885).
Although the rates of renal renin synthesis and secretion can vary significantly within and between individuals,
the density of renin granules in secretory cells is surprisingly constant. For example, in rats under normal laboratory conditions, one renin granule is found, on average, in
a cell volume of 5 ␮m3 (715, 813). A very similar density
was observed during chronic salt depletion when the
overall renin synthesis and secretion are strongly stimulated. Instead of elevating the number of granules per cell,
the total number of renin-producing cells increases during
salt depletion. The gross morphology of renin secretory
granules of newly recruited JG cells is similar to that of
the granules in the control situation. The mouse and rat
renin granules have average volumes of 0.63 (400) and
0.35 ␮m3 (715), respectively. Therefore, the long-term
regulation of renin synthesis and secretion appears to be
mediated by altering the number of renin-producing cells,
rather than by modifying the processes involved in the
control of renin synthesis and secretion in the individual
cell (see sect. IIG).
2. Mechanisms of renin secretion
As in other cells, the early secretory granules in
renin-producing cells can take up extracellular protein by
endocytosis, including horseradish peroxidase, which is
targeted to the early granules without transit through the
Golgi apparatus (865).
The ability to segregate renin into dense-core secretory granules for regulated exocytosis seems to be specific to native JG cells in situ. After isolation, JG cells
rapidly lose the ability to direct renin into this pathway,
and the various renin-producing cell lines (e.g., As4.1,
Calu-6) do not store active renin in secretory granules, but
instead secrete it constitutively.
Physiol Rev • VOL
A substantial amount of evidence indicates that the
regulated release of renin proceeds via traditional exocytotic mechanisms. Thus the spontaneous release of renin
at the cellular level is discontinuous in the renin content
per discharge, which corresponds to the calculated renin
content of one secretory granule (813). Furthermore, the
acute stimulation of renin secretion in vivo, for example,
by renal artery constriction, leads to a marked decrease in
the number of renin storage granules (715), while the
average size of the individual granules does not change.
Elegant in vitro studies using two-photon microscopy
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PHYSIOLOGY OF KIDNEY RENIN
have confirmed the rapid disappearance of renin storage
granules upon the acute stimulation of secretion (687).
Recent support for exocytosis as the pathway for renin
release is derived from capacitance measurements of single renin-producing cells of the kidney. The average capacitance of a mouse JG cell is ⬃3.1 pF (235), yielding a
calculated cell volume of ⬃500 fl (500 ␮m3). Rat cells
have a smaller capacitance of 2.6 pF, reflecting a somewhat smaller cell volume (235, 239).
The other conditions known to stimulate renin secretion in vivo and in vitro (see below) lead to as much as a
15% increase in capacitance, reflecting the insertion of the
vesicle membrane into the plasma membrane (235, 236,
239). It has been estimated from whole cell patch-clamp
studies that the number of granules that are released
within minutes after maximal stimulation constitutes
⬃20% of the total vesicle number. This might indicate the
presence of a pool of immediately available renin storage
granules, the existence of which has also been postulated
from studies of isolated glomeruli (812) and isolated perfused kidneys (486).
The activation of renin secretion is accompanied by
the formation of deep plasma membrane invaginations.
These invaginations likely result from the addition of
membrane material, obtained from many secretory granules, to the cell surface and to already-fused secretory
granules (compound exocytosis) (715, 734). These invaginations may explain why the discharge of the renin secretory vesicles does not necessarily require movement of
the vesicles to the cell perimeter (687).
The molecular events that drive and regulate the
exocytosis of the renin storage vesicles remain unknown.
A single finding in this context is that the renal reninproducing cells express the calcium-dependent activator
protein for secretion (CAPS). This family of proteins is
specifically involved in the secretory process of large
dense-core vesicles but not small clear secretory vesicles
(822).
B. Electrical Properties of Juxtaglomerular Cells
The electrophysiology of renin-producing JG cells
has been investigated in some detail using electrodes or
TABLE
1.
patch-clamp techniques on single JG cells or JG cells in
situ in isolated glomeruli with attached afferent arterioles (recently reviewed in Refs. 236, 238; see also
Table 1).
Vasoconstrictors, which are known to suppress renin
release, depolarize JG cells in situ (96, 97). In addition, an
increase in the extracellular K⫹ concentration or an inhibition of K⫹ channels not only depolarizes JG cells, but
also suppresses renin release (158, 269, 480, 487). On the
other hand, the membrane hyperpolarization induced by
K⫹ channel activation or Cl⫺ channel inhibition is accompanied by a stimulated renin secretion (227, 239, 396, 403,
615). Furthermore, the pharmacological inhibition of the
Na⫹-K⫹-2Cl⫺ cotransport activity using furosemide leads
to the hyperpolarization of single JG cells while concomitantly stimulating renin exocytosis (128). Both effects of
furosemide appeared to depend on the Na⫹-K⫹-2Cl⫺ cotransporter (NKCC1) isoform, since neither was observed
in NKCC1-deficient mice (128). Taken together, there is
good reason to assume that changes of the membrane
potential of JG cells are associated with renin release,
such that depolarization is accompanied by suppressed
renin exocytosis, while hyperpolarization is accompanied
by stimulated renin exocytosis. Despite the clear association between both parameters, it is not clear whether
changes in the membrane potential directly and causally
control renin release.
The depolarization of JG cells in response to vasoconstrictors, such as ANG II, probably results from the
inhibition of inwardly rectifying K⫹ channels (Kir) by a G
protein-mediated process (483). Besides the Kir (235, 483,
507), there is electrophysiological evidence of at least two
additional potassium (K⫹) conductances in JG cells. The
first conductance is associated with a delayed outwardly
rectifying K⫹ current (235, 239, 483) that has been identified as the BKCa zero splice variant; additionally, this
conductance is activated by cAMP and results in hyperpolarization (239). The second conductance is associated
with the KATP channels (732). In addition to potassium
channels, there is good evidence for the presence of
NKCC1 and Ca2⫹-activated chloride channels in the
plasma membrane of JG cells (128, 418, 483). Ca2⫹-activated Cl⫺ channels might contribute to membrane depo-
Expression and function of ion channels in JG cells
Channel
Inward rectifier K⫹ channels; Kir
Ca2⫹-activated K⫹ channels; BKCa zero variant
ATP-sensitive K⫹ channels; KATP
Regulation in JG Cells
Inhibition by angiotensin II
Activation by cAMP
Na⫹-K⫹-2Cl⫺ cotransporter1; NKCC1
Ca2⫹-activated Cl⫺ channels
Voltage-dependent Ca2⫹ channels, L type
Activation by Ca2⫹
Activation by depolarization
Physiol Rev • VOL
Function
Reference Nos.
Depolarization by angiotensin II
Hyperpolarization
Pharmacological activation: hyperpolarization,
stimulation of renin secretion
Pharmacological blockade: hyperpolarization,
stimulation of renin secretion
Depolarization, inhibition of renin secretion
Calcium influx at positive membrane
potentials
4, 92, 229, 468
4, 68, 229, 233
381, 706
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388, 468
233
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CASTROP ET AL.
larization in response to vasoconstrictors. Thus Ca2⫹
mobilization by vasoconstrictors could stimulate Ca2⫹activated Cl⫺ channels, Cl⫺ efflux, and membrane depolarization.
JG cells are strongly electrically coupled to the neighboring cells of the afferent arteriole (96, 483, 732) (see
sect. IIID). Interestingly, their resting membrane potential
changes in situ from ⫺60 to ⫺80 mV in nonpressurized
arterioles (96, 483, 732) to approximately ⫺40 mV in
pressurized arterioles (539). Since the depolarization of
JG cells is accompanied by the suppression of renin release, the depolarization in response to an increase in
perfusion pressure might directly or indirectly contribute
to the known pressure-dependent inhibition of renin secretion.
Since Ca2⫹ inhibits renin secretion, it is clearly possible that the potential-operated Ca2⫹ channels mediate
an influence of membrane potential on renin secretion.
However, functional studies on the role of potential-operated Ca2⫹ channels have produced conflicting results
(159, 487, 764; for a detailed discussion, see Ref. 779). A
recent study by Friis et al. (239) might shed some light on
this controversy; these authors provided evidence for the
presence of L-type Ca2⫹ channel mRNA, protein, and
functional activity in JG cells. However, because these
channels are only activated at very positive membrane
potentials (239), they are unlikely to be operational in JG
cells under physiological conditions. These data might
explain why several studies have failed to detect a direct
functional role of the L-type Ca2⫹ channels in the regulation of renin release (779).
Finally, there is good, albeit indirect, evidence in JG
cells for the store-operated Ca2⫹ entry triggered by the
filling state of the internal Ca2⫹ stores (283, 483, 973). The
identity of the channels underlying this Ca2⫹ influx is
currently unclear. It will be interesting to investigate the
role of ORAI proteins (“calcium release-activated calcium
modulator,” pore-forming subunit of a calcium release
activated calcium channel), as well as TRPC channels, in
the regulation of Ca2⫹ influx and renin release in JG cells,
since these channels contribute to or mediate store-operated Ca2⫹ entry in other cell types (817).
C. Intercellular Contacts of Juxtaglomerular Cells
The different cell types that form the juxtaglomerular
apparatus (JGA) are abundantly coupled via gap junctions
(861, 864). The intense intercellular connection creates a
functional syncytium within this multilayered complex
and may contribute to the regulation of the preglomerular
arteriolar tone, the glomerular filtration rate (GFR), and
the activity of the renin system. Within the JGA, JG cells
form a number of gap junctions among themselves (95),
as well as with their neighboring endothelial, smooth
Physiol Rev • VOL
muscle, or extraglomerular mesangial cells (583, 859, 861,
864).
Gap junctions are made up of connexin (Cx) proteins, which comprise a family of at least 20 protein
isoforms (818). It was recently shown that JG cells predominantly express connexin 40 (Cx40) and, to a lesser
extent, Cx37 and Cx43 (31, 296, 364, 983). The coexpression of Cx40 with Cx37 and Cx43 is specific to renin cells
in the typical juxtaglomerular position, as renin-producing cells situated outside the classic juxtaglomerular position express only Cx40. Thus fetal renin-producing cells,
which are still located in the wall of the larger renal
arteries (756), and renin cells recruited upstream along
the afferent arteriole by chronic challenge of the renin
system showed only a Cx40-mediated coupling. For this
reason, Cx40 may be considered as a fundamental feature
of renin-producing cells (492). In addition to being found
in renin-producing cells, Cx40 has been detected as one of
the four main connexins (Cx37, Cx40, Cx43, Cx45) expressed in the wall of renal vessels (191, 290), where it is
found almost exclusively in the endothelium.
Our knowledge of Cx40 expression in renin-producing cells has been mainly obtained from morphological
analyses, and the functional relevance has not yet been
extensively studied. However, one could imagine that the
Cx40-mediated junctions between JG cells and the adjacent endothelium or the extraglomerular mesangium
might provide a suitable pathway for the propagation of
blood-borne or macula densa-derived signals involved in
the control of the renin system.
Mice harboring a genetically disrupted Cx40 gene
have been useful tools for investigating the functional
importance of this connexin. Cx40 knockout mice are
hypertensive (185) and show a high renin status (465,
922). An obvious explanation for the unusual combination
of high renin levels with high blood pressure is that the
transmission of inhibitory signals to JG cells does not
work in the absence of Cx40. In fact, studies have shown
that the classic negative-feedback mechanisms of renin
secretion and renin gene expression exerted by ANG II or
intrarenal blood pressure are disturbed in Cx40-deficient
mice (465, 922); these data support the model of Cx40dependent transmission of inhibitory signals to JG cells.
Experimental unilateral renal stenosis in Cx40 knockout
mice did not lead to the increase in blood pressure or
elevated plasma renin levels that would typically be observed in wild-type mice. Furthermore, the typical increase in renin mRNA in the kidney with impaired perfusion is absent in Cx40 knockout kidneys. However,
whether the special importance of Cx40 in JG cells is
related to the unique properties of this connexin remained
uncertain and was subsequently addressed by Cx40
knock-in Cx45 (Cx40KI45) mice. In these mice, the coding
region for Cx40 was replaced by Cx45 under the control
of the native Cx40 promoter (12). Cx45 exhibits a lower
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conductance than Cx40, and it is not normally expressed
in JG cells (492, 780). Interestingly, Cx40KI45 mice
showed a reestablishment of the interrupted physiological feedback control by ANG II and intrarenal pressure,
and the mice were consequently protected against hypertension, which was observed in the general Cx40 knockout model (780). Renin-producing cells in the Cx40KI45
mice are, at first glance, associated with the juxtaglomerular regions of the afferent arterioles. A more detailed
analysis, however, revealed that the arrangement of the
renin-producing cells is not completely normal (490).
Other previous studies in the Cx40KI45 mice described
the unique functions of Cx40 in certain tissues (12, 956).
The compatibility of Cx40 with Cx45 in JG cells, however,
shows that at least the conduction of inhibitory signals
involved in the control of renin secretion and renin mRNA
expression does not rely on the specific properties of
Cx40.
Intriguingly, the regulation of the renin system by salt
intake (see sect. VA) appears not to be fundamentally
deteriorated in the absence of Cx40. In both wild-type
mice and Cx40-deficient mice, the plasma renin concentrations and renin mRNA levels were inversely related to
the salt load (465, 922). At the same time, catecholamines,
the classic stimulators of the renin system, appear to
function quite normally (922), suggesting that renin does
not escape from physiological control in the absence of
Cx40.
The question remains as to whether other regulators
of the renin system, such as prostanoids or nitric oxide
(NO), function normally when the Cx40 gene is disrupted.
Investigations into the involvement of cyclooxygenase
(COX)-2-derived prostanoids have revealed a clear increase in the expression of COX-2 mRNA and protein
levels in mice lacking Cx40 (464, 921), which underlines
the parallel control mechanism of renin and COX-2 genes
by the macula densa cells (127, 769). The treatment with
COX-2 inhibitors markedly reduced renin mRNA levels in
Cx40-deficient mice, similar to wild-type mice, and diminished the increase in the number of renin-producing cells
(921). Similar results were obtained in experiments examining the involvement of the macula densa-derived NO
in the regulation of renin expression in mice lacking Cx40.
The kidneys of the Cx40 knockout mice demonstrate a
large increase in the expression of the neuronal nitric
oxide synthase isoform (nNOS) and show decreased renin levels after the pharmacological inhibition of NOS
activity (464). These observations demonstrate that COX2-derived prostaglandins and NO act as tonic stimulators
of the renin system in the kidney of both normal and Cx40
knockout mice. One could speculate that the strongly
elevated levels of COX-2 and nNOS contribute to the
excessive renin secretion and synthesis observed in the
absence of Cx40.
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In addition to these functional consequences, the structure and positioning of renin-producing cells in the JG position is strikingly altered in Cx40 knockout mice (493). Reninproducing cells are typically located in the media layer of the
afferent arteriole, close to the vascular pole of the glomerulus. Although renin-producing cells display a high degree of
plasticity during renal development (756) and chronic stimulation of the renin system (see sect. II, E and F), they are
normally integrated into the wall of the arterial vessels.
Ectopic renin expression in cells outside the medial layer
of arteries has been described as a rare event that occurs,
if at all, in the extraglomerular mesangium (457). In kidneys lacking Cx40, renin-producing cells are absent from
the wall of the afferent arterioles. Instead, they are found
around the wall of the afferent arterioles, extending into
the region of the extraglomerular mesangium and the
periglomerular interstitium. These ectopic renin-producing cells do not show the typical epithelioid appearance,
instead exhibiting a more irregular mesenchymal-like
shape. Interestingly, the expression of renin in the developing kidney of Cx40 knockout mice is restricted to the
walls of the larger arteries, and it does not appear in the
interstitial space until the wave of renin expression shifting along the arterial tree during nephrogenesis finally
reaches the glomerulus (493). One may, therefore, speculate that Cx40 is required for the correct “homing” of
renin-producing cells in the JGA. It remains to be determined whether the Cx40-mediated contacts act as transmembrane channels that conduct unidentified signals relevant for the differentiation and proliferation of JG cells
or whether they function as scaffolds that enable the
correct assembly of other proteins relevant to the positioning of renin-producing cells in the classic location
(216).
Apart from Cx40, JG cells also express Cx37 and
Cx43 (492). Cx37 expression is not coregulated with Cx40
when the renin system is stimulated (465), but it cannot
be demonstrated in renin-producing cells in the absence
of Cx40. In contrast to mice lacking Cx40, Cx37-deficient
mice are normotensive (807), suggesting that Cx37 might
be less relevant for JG cell function than Cx40. In fact, our
preliminary information suggests that the renin system
works quite normally in the Cx37-deficient mice (926).
The role of Cx43 in the function of JG cells is at
present less clear. Mice in which Cx43 is replaced by Cx32
(Cx43KI32 mice) displayed markedly lower renin levels
than the wild-type controls (295). Notably, the reduction
of renal perfusion pressure by unilateral renal artery stenosis, which normally leads to an increase in renin secretion and synthesis in the affected kidney and decreases
renin content in the contralateral intact kidney, did not
affect the renin expression in Cx43KI32 mice. This observation might indicate that, in addition to Cx40, Cx43 might
also be critically involved in the control of the renin
system. In summary, the intercellular signaling via con-
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nexins appears to be an important determinant for the
control of the renin system and for normal localization of
JG cells.
D. Intracellular Signals Controlling Renin Release
At the cellular level, the numerous systemic and local
factors that regulate renin release merge into three intracellular second messenger systems: the cAMP, cGMP, and
calcium (Ca2⫹) pathways (Fig. 4).
1. cAMP
Undoubtedly, cAMP is the central intracellular stimulator of renin release. This conclusion is supported by
several lines of indirect and direct evidence. For instance,
the activation of ␤-adrenoreceptors, which are known to
enhance adenylyl cyclase activity, stimulates the renin
secretion in a broad range of experimental in vitro models, including single JG cells as well as in vivo (54, 235,
423, 484, 903, 944). Moreover, the renin release in response to renal nerve stimulation is mediated by the
␤-adrenoreceptors (349), and ␤1/␤2-adrenoreceptor
knockout mice possess low plasma renin concentrations (PRC) (434). [Note that PRC is measured as the
rate of ANG I generation in the presence of excess renin
substrate. Plasma renin activity (PRA) is measured as the
generation of ANG I without the addition of exogenous
renin substrate.] In addition to catecholamines, other hormones, such as the prostaglandins E2 and I2 (prostacyclin) (402), dopamine (476), calcitonin gene-related peptide (482), pituitary adenylyl cyclase activating polypeptide (PACAP) (322), and adrenomedullin (397), stimulate
the renin release from isolated JG cells and increase the
intracellular cAMP concentrations.
The stimulation of adenylyl cyclase activity in response to activation of G protein-coupled receptors is
mediated via the stimulatory G protein Gs␣. In line with
the stimulatory role of Gs␣ and cAMP for renin release,
the PRC is markedly reduced in mice carrying a conditional deletion of Gs␣ in JG cells (146). Notably, PRC is
not stimulated in the Gs␣ KO mice in response to catecholamines, inhibition of the macula densa mechanism,
or a drop in blood pressure, underscoring the central role
of the cAMP pathway in the regulation of renin release
(146).
Additionally, the direct activation of adenylyl cyclase
activity by the diterpen forskolin strongly increases cAMP
levels and renin release in isolated JG cells (283, 484), as
well as in the renin-producing cell line As4.1 (283, 442).
Finally, a direct link between cytosolic cAMP levels and
renin release was demonstrated by the fact that mem-
FIG. 4. Intracellular signaling pathways controlling the renin exocytosis. ANP, atrial natriuretic peptide; AC5/6, adenylate cyclases 5/6; cGK,
protein kinase G; DAG, diacylglycerol; GC-A, guanylate cyclase A (particulate guanylate cyclase); GP, GTP-binding protein; IP3, insitol 1,4,5trisphosphate; NO, nitric oxide; PDE3a, cAMP-phosphodiesterase 3a; PKA, protein kinase A; PKC, protein kinase C; PLC, phospholipase C; sGC,
soluble guanylate cyclase.
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brane-permeable cAMP analogs and direct intracellular
applications of cAMP via a patch pipette rapidly stimulate
renin secretion (235).
Intracellular cAMP levels are determined not only by
cAMP formation, but also by cAMP hydrolysis to 5⬘-AMP
through the activity of cAMP phosphodiesterases (PDEs).
The inhibition of cAMP degradation, either by nonselective inhibition of PDE activity using xanthine derivatives,
such as 3-isobutyl-1-methylxanthine (IBMX) or theophylline, or by selective blockers of the isoforms PDE-1,
PDE-3, and PDE-4, stimulates renin release (154, 156, 157,
479). Moreover, strong expression of PDE-3 and PDE-4
was confirmed in single JG cells and in the JG cell line
As4.1 (237, 442). PDE-3 activity is regulated by cGMP,
with an increase in the cytosolic cGMP inhibiting PDE-3
activity, which eventually results in elevated cAMP levels
(57). Via this pathway, cGMP can indirectly stimulate
renin secretion, which is of major physiological importance for the influence of NO on renin release (see below).
In conclusion, numerous studies using different approaches have clearly indicated that cAMP is the central
stimulator of renin release. However, little is known about
the mechanisms through which cAMP triggers the exocytosis of renin storage vesicles. While it has been shown
that the stimulation of renin release by cAMP involves a
PKA-dependent step (237, 477), the phosphorylation targets of PKA in JG cells are currently mostly unknown. It
has recently been reported that JG cells express functional cAMP-sensitive BKCa channels and that the activation of these channels by cAMP results in hyperpolarization of the cells (239). As discussed earlier, the hyperpolarization of JG cells appears to favor exocytosis,
suggesting that the activation of BKCa channels by cAMP
might lead to enhanced renin exocytosis. However, the
pharmacological inhibition of the BKCa channels does not
attenuate the stimulation of renin release in response to
cAMP (239). Therefore, a future challenge will be to identify the downstream signaling events that mediate the
stimulation of renin exocytosis by the cAMP/PKA pathway.
2. Calcium
While cAMP is the main stimulator of renin release,
the free cytosolic Ca2⫹ concentration is considered as the
primary inhibitor. Notably, an increase in the intracellular
Ca2⫹ concentration initiates and supports exocytosis in
all other secretory cells, excluding parathyroid gland cells
(165). Accordingly, the unusual effect of Ca2⫹ in the reninsecreting JG cells has been termed as the “calcium paradox” of renin release.
Early indirect evidence for an inhibitory influence of
calcium on renin secretion was obtained from the observation that classical vasoconstrictors suppress renin rePhysiol Rev • VOL
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lease (293, 779). Thus vasoconstrictors such as angiotensin II, endothelin, vasopressin, and norepinephrine not
only increase the Ca2⫹ influx or intracellular Ca2⫹ levels
in JG cells (283, 369, 484, 485), but they also inhibit the
renin release in a Ca2⫹-dependent fashion (587, 843).
Other measures that result in an elevation of the cytosolic
Ca2⫹ concentration also suppress renin release. For instance, thapsigargin, which blocks the sarcoendoplasmic
Ca2⫹-ATPases and induces the store-operated Ca2⫹ influx, elevates the intracellular Ca2⫹ concentration in JG
cells and suppresses renin release from isolated perfused
kidneys and cultured JG cells (283, 781, 973). Conversely, the chelation of intracellular Ca2⫹ using 1,2bis(2-aminophenoxy)ethane-N,N,N⬘,N⬘-tetraacetic acid
(BAPTA) stimulates renin release from isolated juxtaglomerular cells (587, 654, 655).
Extracellular and intracellular calcium concentrations are positively correlated in JG cells (483). Therefore,
it was correctly predicted that lowering the extracellular
Ca2⫹ concentration would stimulate renin secretion in
several in vitro models (293, 488, 863) and that the infusion of Ca2⫹ would suppress renin secretion from the
nonfiltering kidneys of dogs in vivo (940). In addition to
the parallel changes in the extra- and intracellular Ca2⫹
concentrations, the Ca2⫹-sensing receptor, which also
controls the release of the parathyroid hormone in a
Ca2⫹-dependent fashion, may participate in the regulation
of renin release by the extracellular Ca2⫹ concentration
(653).
Similar to the stimulation of renin release by cAMP,
the downstream signaling pathways that mediate the suppression of renin exocytosis in response to an elevation in
the cytosolic Ca2⫹ concentration are still under investigation. There is evidence to suggest that the suppression of
renin release by Ca2⫹ involves the following: 1) Ca2⫹/
calmodulin-dependent processes, such as the activation
of myosin light chain kinase; 2) the modulation of ion
channel activities in the plasma membrane or in the membrane of the renin-containing granule; or 3) the activation
of PKC.
Since these studies have been the subject of previous
reviews (293, 473, 779), we focus on a further downstream
target of Ca2⫹, namely, the Ca2⫹-inhibited adenylyl cyclases AC5 and AC6 (283, 655). Both AC5 and AC6 are
inhibited by physiological increases in the intracellular
calcium concentrations and are therefore well positioned
to link the inhibitory calcium pathway to the stimulatory
cAMP pathway in an inverse manner in JG cells. In fact,
the expression of AC5 and AC6 mRNA has been found in
JG cells, while protein expression in these cells has so far
been demonstrated only for AC5 (283, 654, 935). Moreover, an inverse relationship between the cytosolic Ca2⫹
and cAMP levels has been found in primary cultures of JG
cells. While the increase in intracellular Ca2⫹ that occurred in response to endothelin-1, ANG II, or thapsigar-
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CASTROP ET AL.
gin was paralleled by a reduction of the intracellular
cAMP levels and renin release (283), the intracellular
Ca2⫹ chelator BAPTA-AM had the opposite effect (654,
655). Since the inverse relationship between intracellular
Ca2⫹ and renin release was prevented by clamping the
intracellular cAMP levels or by the inhibition of adenylyl
cyclase activity, these data suggest that the modulation of
cAMP by Ca2⫹ is an important determinant of the inverse
relation between calcium and renin release (283, 655).
The functional role of AC inhibition by Ca2⫹ has been
further corroborated in gene knockdown studies (283)
and in pharmacological studies using the adenylyl cyclase
inhibitor NKY-80, which shows preferential binding to
AC5 compared with the non-calcium-inhibited isoforms
AC2 or AC3 (648, 654).
Although the inhibition of cAMP formation by Ca2⫹
provides a possible explanation for the calcium paradox,
future work should attempt to verify the functional roles
of AC5 and AC6 in more complex models and in vivo,
since the regulation of adenylyl cyclase activity does not
appear to completely explain the calcium paradox at the
whole organ level (283). Moreover, further studies are
needed to integrate other factors known to contribute to
the Ca2⫹-dependent inhibition of renin release, such as
the activation of the myosin light-chain kinase or the
modulation of channel activity, into this model of Ca2⫹inhibited adenylyl cyclases mediation of the calcium paradox.
3. cGMP
In contrast to cAMP and Ca2⫹, which have been
unequivocally shown to either stimulate or suppress renin
release, the effects of cGMP are more complex, given that
it can both stimulate and inhibit renin secretion.
On one hand, the application of membrane-permeable cGMP analogs at high concentrations suppresses
renin release in a variety of models, including dispersed
JG cells (276, 332, 475, 477, 633, 771). On the other hand,
unmodified cGMP stimulates renin exocytosis upon direct
injection into single JG cells (237). These contradictory
effects can be best explained by the different affinities of
each type of cGMP for intracellular target molecules.
While cAMP-degrading phosphodiesterases such as
PDE-3 are inhibited more efficiently by cGMP than by the
stable cGMP analogs, the latter show a much higher affinity for cGMP-activated kinases (cGKs) (108). Therefore, these data indicate that cGMP can either stimulate
renin release via the inhibition of PDEs or suppress renin
secretion via cGK-dependent processes.
In fact, the cGMP-inhibited PDE-3 plays a mediator
role in the stimulation of renin release by NO. Although
the data are not unequivocal, NO has been shown to
stimulate renin release in a variety of in vitro models, as
well as in vivo (489). This stimulatory effect of NO is
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mimicked by the pharmacological inhibition of PDE-3, a
PDE isoform that hydrolyzes cAMP (156, 157, 237, 479).
Moreover, NO donors increase both intracellular cAMP
concentration and renin secretion in primary cultures of
JG cells, similar to the effects of PDE-3 inhibitors (477).
These data suggest the existence of a cascade of signaling
events connecting the cGMP and cAMP pathways in JG
cells, where NO stimulates the formation of cGMP, which
in turn suppresses PDE-3 activity and cAMP hydrolysis.
Since cAMP is the central stimulator of renin release, the
resulting intracellular accumulation of cAMP eventually
enhances renin exocytosis. In fact, this interplay between
the cGMP and cAMP pathways has been confirmed in vivo
(59) in isolated perfused kidneys (479) and in patch-clamp
experiments using single JG cells, in which cGMP stimulated renin exocytosis in a PDE3-, cAMP-, and PKA-dependent manner (237).
In addition to PDE-3, JG cells express cGK. cGKI is
found in the cytosol, while cGKII is associated with renin
granules (253, 254). Stable cGMP analogs suppress renin
release in isolated perfused kidneys and in microdissected glomeruli with attached afferent arterioles (254,
927). As mentioned above, the stable cGMP analogs show
a high affinity for protein kinase G. Accordingly, the suppression of renin release by these compounds is completely prevented by the pharmacological inhibition of the
cGKs (254). Moreover, cGMP analogs inhibit renin secretion in the primary cultures of JG cells isolated from
wild-type or cGKI-deficient kidneys, but not from cGKIIdeficient kidneys (254, 927). Therefore, it can be concluded that cGMP can inhibit renin release via the activation of cGKII. The downstream targets of cGKII that
eventually interfere with the exocytosis of renin storage
granules are presently unknown.
The dual effects of cGMP on renin release raise the
question of which factors determine whether endogenous
cGMP stimulates or inhibits renin secretion. It is possible
that the effects of cGMP depend on its intracellular concentration. Since low concentrations of cGMP preferentially inhibit PDE-3, the stimulation of renin release would
occur. In contrast, high concentrations of cGMP can also
activate cGKII. Since cGKII activation can, in principle,
attenuate the stimulation of renin release in response to
cAMP (489), a high concentration of cGMP would suppress renin release. Moreover, it appears likely that the
stimulatory and inhibitory cGMP pathways are spatially
segregated from each other. This hypothesis is consistent
with the intracellular localization of the cGMP-generating
guanylate cyclases and cGMP target enzymes. Soluble
guanylate cyclase (sGC) is a cytosolic enzyme like PDE-3;
as a result, the cGMP derived from sGC may predominantly stimulate renin secretion via the cAMP pathway.
Since NO activates sGC, this pathway could provide an
explanation for the stimulation of renin release by NO. In
contrast to sGC, the membrane-bound particulate guany-
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623
late cyclase (pGC) is found in close proximity to the
vesicles associated with cGKII. Since cGMP derived from
pGC would therefore inhibit renin secretion, this pathway
could explain the inhibition of renin release in response to
atrial natriuretic peptide (ANP) (see sect. VC4). Such a
spatial segregation of cGMP signals induced by ANP and
NO occurs in both HEK cells and vascular smooth muscle
cells (623, 695), although no data supporting this hypothesis in JG cells are presently available.
IV. LOCAL CONTROL OF RENIN SECRETION
As will be outlined in section V, renin secretion is
modulated by multiple systemic factors. In addition, the
presence of renin-generating granular cells at the distal
portion of the afferent arteriole enables the adjacent or
nearby cells to exert a local control over the renin secretion. These local control mechanisms of renin secretion
comprise tubular, vascular, and nervous components
(Fig. 5). In addition to unambiguously locally generated
factors, there are hormones such as ANP and ANG II that
may be of local and/or systemic origin; those factors will
be covered in section V.
A. Tubular Control of Renin Secretion
Renin secretion from the granular cells of the afferent arteriole is locally influenced by the tubular system of
the corresponding nephron. The anatomical basis of this
regulatory pathway for renin secretion resides in the close
linkage of the tubular and vascular system within the
confines of the JGA. Specifically, the thick ascending limb
of Henle’ loop (TAL) emerging from the renal medulla
comes into close contact with its parent glomerulus. This
anatomical link between the tubular system and the vasculature of the afferent and efferent arterioles enables the
specialized tubular cells of the cortical thick ascending
limb of Henle’s loop (cTAL) and the macula densa (MD)
cells located adjacent to the extraglomerular mesangium
to influence renin secretion. In this local control system,
changes in the tubular NaCl concentration are translated
into inverse changes in renin secretion. Early experimental evidence for a tubular control mechanism of renin
secretion has been reviewed elsewhere (293), but the
most striking and direct evidence was provided by the
following in vitro experiment. Rabbit JGAs were isolated,
and TALs were perfused with artificial tubular fluid containing various concentrations of NaCl. Simultaneously,
the entire JGA was superfused, and renin release was
determined by microassay. In this experimental setup, a
decrease in the tubular NaCl concentration resulted in “a
prompt stimulation of the renin release rate” (815). This
fundamental finding sparked interest in the signaling
pathways that link the tubular NaCl concentration and
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FIG. 5. Local control of the renin secretion. The renin-generating
granular cells are located at the distal portion of the afferent arteriole.
The cells adjacent to the granular cells or in their close vicinity exert a
local control on the renin secretion. These local control mechanisms of
renin secretion comprise vascular, nervous, and tubular components.
The stimulatory factors like nitric oxide (NO; formed by endothelial NO
synthase) and prostacyclin/prostaglandin E2 are formed in the endothelium adjacent to the granular cells. They are counteracted by the inhibitory factors like endothelins. The overall effect of the sympathetic input
derived from local nerve endings and circulating catecholamines is
stimulatory. The prostanoids (stimulatory) and ATP (inhibitory) are
generated by the tubular macula densa cells under the control of the
NKCC2-dependent salt transport activity. The macula densa salt transport in this system is translated into an increased formation and release
of prostanoids and ATP in response to the low and high tubular salt
concentration, respectively. In addition, the tubular macula densa cells
constitute a rich source of NO (formed by neuronal NO synthase), which
provides a background stimulus for the renin secretion.
renin secretion. The initial step of the MD-dependent
control of renin secretion is the detection of the NaCl
concentration in the tubular lumen by the MD cells. The
transport activity of the Na⫹-K⫹-2Cl⫺ cotransporter
NKCC2 (BSC1) in the apical membrane of these cells is
thought to be the primary mechanism by which the MD
cells detect the tubular NaCl concentration (64, 65, 500,
538, 640, 758, 958). In addition, the NaCl transport activity
mediated by NHE2 might contribute to the MD salt sensing (306). The MD cells subsequently transmit information
about the tubular NaCl concentration to the granular cells
of the afferent arteriole to influence renin secretion.
Three likely candidate molecules have been proposed to
serve as mediators of the MD-dependent control of renin
secretion: prostanoids, NO, and adenosine/ATP. These
molecules meet the key criteria to serve as signal mediators between tubular epithelial cells and JG cells of the
afferent arteriole: 1) MD cells have the capacity to gener-
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CASTROP ET AL.
ate each molecule, 2) their formation depends on the
tubular salt concentration, and 3) there is solid experimental evidence to suggest that they directly influence
renin secretion.
1. Prostanoids
Prostanoids are generated from arachidonic acid in a
two-step reaction. The first step, the formation of prostaglandin H2 (PGH2), is catalyzed by two isoforms of cyclooxygenases, the constitutively expressed COX-1 and
the inducible COX-2 (171, 660). PGH2 is subsequently
modified by the various prostanoid synthases to produce
specific prostanoids. Of those, prostaglandin E2 (PGE2)
and prostacyclin (PGI2) were shown to directly stimulate
renin secretion in isolated JG cells (241, 401).
A) ACTIVATION OF EP2, EP4, AND IP RECEPTORS STIMULATES
RENIN SECRETION.
In vitro investigations and studies in mice
with a specific deletion of single prostanoid receptors
revealed that the stimulation of renin secretion by PGE2
and PGI2 are mediated via EP2, EP4, and IP receptors
(241, 244, 778). EP2, EP4, and IP prostanoid receptors are
all coupled to Gs-mediated increases in intracellular
cAMP, which act as the main stimulus of renin secretion
(see sect. IIC1).
B) PROSTANOID GENERATION IN THE TAL. Regarding the concept of local tubular control of the renin system, Harris et
al. (315) first described the constitutive expression of
COX-2 in MD cells of the rat. This finding suggested that
COX-2-derived prostanoids might be involved in the MD
control of renin secretion. An in-depth analysis of COX-2
expression in the cortical TAL by immunohistochemistry
revealed that COX-2 expression in rats and rabbits is not
restricted to the MD cells but is also found in the adjacent
tubular cells of the TAL (151, 558, 866, 916). COX-2 expression in the TAL of primates and humans appears to be
low compared with rodents, at least under normal conditions (429, 452, 621, 867). It should be noted in this
context, however, that the typical diet in the Western
hemisphere is rich in NaCl and that, as outlined later,
COX-2 expression is suppressed by a high oral salt intake,
which may thus impair the detection of COX-2 in human
renal cortices by immunohistochemistry. In addition to
COX-2, the MD cells also express the microsomal isoform
of PGE2 synthases (867), rendering MD cells capable of
generating PGE2 (113, 250, 867, 917). The expression of
PGE2 synthases in MD cells has been detected in both
humans and rodents (113, 867). Functional evidence for
the generation of PGE2 by MD cells was obtained using
biosensor cells in isolated JGA preparations. In this setup,
HEK293 cells transfected with the PGE2 receptor EP1
were positioned close to MD cells, and a release of PGE2
was detected via an increase in intracellular calcium of
the biosensor cell; furthermore, this effect was specific
for MD cells (689).
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C) COX-2 EXPRESSION AND ACTIVITY IN THE TAL ARE REGULATED.
The constitutive generation of prostanoids by MD cells
would allow for a tonic influence on renin secretion by JG
cells. However, the expression of COX-2 in the MD cells
and the acute formation of prostanoids are regulated by
physiological stimuli, making it feasible that the MD-derived prostanoids could be involved in the signal transmission between the epithelial MD and vascular JG cells.
Most strikingly, the regulation of COX-2 is usually paralleled by corresponding changes in the activity of the renin
system. Thus COX-2 mRNA expression in the MD is upregulated upon chronic administration of loop diuretics
(131, 414, 415). Similarly, Bartter patients (these patients
suffer from loss-of-function mutations of NKCC2, or other
crucial proteins for TAL NaCl reabsorption, such as ClCNKB, ROMK, or Barttin) show markedly increased COX-2
expression in the cTAL, indicating a relationship between
the NKCC2-dependent salt transport and COX-2 expression (453). COX-2 expression was also found to be increased under conditions of reduced oral salt intake or
diminished renal perfusion pressure, both of which might
result in a reduced distal TAL salt concentration (315, 318,
398, 955, 972). In addition, the enhanced expression of
COX-2 observed in conditions of both reduced oral salt
intake and compromised TAL salt transport activity (loop
diuretics, Bartter’s patients) was paralleled by an increase
in the expression of the microsomal PGE2 synthase, the
downstream enzyme of PGE2 synthesis (113, 454).
Whereas changes in prostanoid production due to the
altered expression of COX-2 and accessory downstream
enzymes are likely to influence renin secretion over
longer time frames, an acute reduction of salt concentration in MD cells was shown to result in rapid changes in
the prostanoid formation, presumably related to changes
in COX-2 and PGE2 synthase activity. In this context,
in vitro experiments using the aforementioned biosensor
approach indicated a release of PGE2 across the basolateral membrane of the MD cells in response to a decreased
tubular salt concentration or in response to the presence
of loop diuretics (689). Such acute changes in the prostanoid formation require the presence of sufficient amounts
of substrate, i.e., arachidonic acid. Whether these changes
in phospholipase A2 activity are causally involved in the
modulation of the tubular prostanoid formation awaits
experimental evaluation.
D) COX-2-DERIVED PROSTANOIDS AND RENIN SECRETION. Both
in vitro and in vivo studies were performed to assess the
functional relevance of prostanoid release from the MD
cells in the control of renin secretion. The in vitro experiments using isolated TAL/JGA preparations indicated a
crucial role for MD prostanoid formation in the stimulation of renin secretion in response to a reduction in the
salt concentration in the tubular perfusion fluid; that is,
the nonselective blockade of COX activity blunted the
increase in renin secretion following a reduction of the
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tubular salt concentration (277). Similar results were obtained with the COX-2 inhibitor NS-398, whereas COX-1
inhibition had no effect (890). All attempts to assess the
in vivo role of locally generated prostanoids in the regulation
of renin secretion have been hampered by the lack of experimental tools to specifically or locally modulate the
prostanoid formation within the confines of the JGA without inducing systemic effects. For example, the blockade
of COX-2 activity during the inhibition of NKCC2 transport activity by the administration of loop diuretics markedly reduced the typical stimulation of renin secretion
(414, 768). However, the reduced renin secretory response under loop diuretic treatment was accompanied
by a considerably moderated diuretic effect of the loop
diuretic, thus permitting no clear conclusion as to
whether the blunted stimulation of renin secretion was
directly or indirectly related to the COX inhibition. Similar
results were found in humans with genetic inactivation of
NKCC2: in type 1 Bartter’s patients, plasma renin activity
and abnormal natriuresis/diuresis were both ameliorated
by the specific inhibition of COX-2 with rofecoxib (723).
In healthy volunteers, COX-2 inhibition by rofecoxib was
shown to block the increase in PRA in response to a
salt-restricted diet (414). Initial animal experiments in
rats and mice have suggested that the stimulation of renin
secretion in response to various experimental maneuvers,
including renal artery stenosis, ACE inhibition, AT1 receptor antagonism, and a salt-restricted diet, all depend on
the intact COX-2-dependent prostanoid formation (311,
312, 934). In these early studies, experimental COX-2
inhibitors like NS398 and SC58236 were used. Follow-up
studies using the Food and Drug Administration-approved
COX-2 inhibitors rofecoxib or celecoxib were not able to
fully confirm the initial results of reduced stimulation of
renin secretion after oral salt restriction and after angiotensin antagonism (343, 346, 414). The somewhat contradictory results of the studies that sought to assess the
in vivo role of prostanoids in the MD control of renin
secretion might be attributed to a problem that appears to
be inherent to all attempts to investigate the tubular control of renin secretion. More specifically, to date, we are
not aware of any experimental protocol to specifically
manipulate (which means reduce in the case of the stimulatory signaling pathway) the salt concentration at the
MD segment of the TAL without causing systemic effects
that, in turn, also affect the renin secretion.
The availability of COX-2-deficient mice provided a
fresh impetus for the investigation of the tubular control
of renin secretion. COX-2-deficient mice show markedly
reduced baseline renin expression and secretion (152,
435, 969). In addition, the stimulation of renin secretion
due to reduced oral salt intake, ACE inhibition, angiotensin AT1 receptor antagonism, and reduced renal perfusion
pressure was reduced in COX-2 ⫺/⫺ mice compared with
controls (152, 435, 969). Thus it was tempting to suggest
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that at least the MD-dependent component of the regulation of renin secretion under these conditions is highly
dependent on the COX-2-dependent formation of prostanoids. However, the interpretation of the results was hampered by the fact that the COX-2 ⫺/⫺ mice suffer from
retardation of renal development and considerable deterioration of renal function during adulthood (199, 600);
additionally, the latter was shown to be highly dependent
on the genetic background of the COX-2-deficient strain
(971). Therefore, the regulation of renin secretion in
COX-2 knockout mice was recently revisited in a study
using COX-2-deficient mice of various genetic backgrounds (435). The baseline plasma renin concentration
was reduced to some degree in all COX-2 ⫺/⫺ strains
compared with the corresponding wild-type mice. Similarly, the renin secretory response to acute challenges like
the administration of furosemide, ACE inhibitor, AT1 receptor antagonist, or isoproterenol was unanimously
compromised in the COX-2 ⫺/⫺ mice compared with
controls. However, when the baseline PRC of the COX-2deficient mice was chronically augmented by pretreatment
with a combination of an ACE inhibitor and a low-salt diet,
the acute stimulation of renin secretion in response to furosemide was partially reestablished, suggesting that the COX2-derived prostanoids are responsible in vivo for determining the size of the releasable pool of renin, which eventually defines the amount of renin that can be secreted
during acute stimuli (435). Similar results were obtained
in rats using the COX-2 inhibitor SC58236 (569), again
indicating that COX-2-derived prostanoids act as general
enhancers of the renin system, rather than as mediators of
the regulatory input.
How can these results be reconciled with the credible
in vitro data unequivocally showing that intact COX-2
activity is an indispensable prerequisite for the modulation of renin secretion in response to acute changes in the
tubular salt concentration? Although this question cannot
be answered comprehensively at the moment, accumulating evidence indicates that the role of the tubular control
of renin secretion during chronic variations of the tubular
salt concentration (e.g., chronic changes in oral salt intake) is limited, or it can be compensated for by other
presumably systemic control mechanisms, which are absent in the situation of the in vitro JGA preparation;
conversely, the MD seems to play a crucial role in the
acute (inhibitory) control of renin secretion in vivo (435,
651, 652). We will further address this issue when we
discuss the role of adenosine in the tubular control of
renin secretion.
In summary, prostanoids like PGE2 and PGI2 are
formed by tubular MD cells, and their generation is dependent on tubular salt concentration. PGE2 and PGI2 are
potent stimulators of renin secretion and determine the
operating point of the renin system in vivo. Their relevance as stimulatory mediators of a communication path-
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way between the TAL and JG cells in vitro (i.e., in the
absence of other regulatory mechanisms) is well established, although their significance as regulatory factors of
renin secretion in vivo is less clear.
2. NO
NO activates both inhibitory and stimulatory pathways of renin secretion in the granular JG cells, as outlined in detail in section III. However, with all of the
relevant data taken together, it now appears well established that the overall effect of NO on renin secretion, at
least as far as the in vivo situation is concerned, is stimulatory (407, 683, 765, 770).
A) NOS IN THE VICINITY OF RENIN-GENERATING CELLS. The
formation of NO from L-arginine is catalyzed by three
different NOS isoforms (936, 937). At least two of the
three known NOS isoforms are expressed in close vicinity
to the granular cells of the afferent arteriole. Endothelial
NOS (eNOS) is localized to the endothelial cells of the
afferent arteriole, and nNOS is found in the MD of the TAL
(608, 952). Commensurate with a possible role of NO as
the mediator of MD-dependent regulatory input on renin
secretion, the expression of nNOS in the MD was shown
to be regulated in parallel with the expression of renin
under various conditions, including the variation of oral
salt intake, administration of loop diuretics, and renal
hypoperfusion (84, 126, 611, 772, 808, 886).
B) MACULA DENSA NO FORMATION AND RENIN SECRETION. A
role for NO as a mediator of the MD-dependent stimulation of renin secretion was first suggested in a study that
utilized isolated perfused JGA preparations (326). The
increase in renin secretion observed in response to a
low-salt concentration in the artificial perfusate of the
TAL was markedly attenuated in the presence of the
nonspecific NOS inhibitor NG-nitro- L-arginine (326). For
in vivo studies with the specific nNOS inhibitor 7-nitroindazole (7-NI), the results were less clear. More specifically, some studies reported that 7-NI was capable of
eliminating or at least reducing the effect of a low-salt diet
on the renin system (60, 854), whereas another study
found no influence of 7-NI on the renal renin content
given a salt-restricted diet (312). Several studies have
assessed the effect of NOS inhibition on the stimulation of
renin secretion caused by loop diuretics, which were used
as a measure to address the MD-dependent control of
renin secretion (325). In an isolated renal vessel preparation, NOS inhibition substantially reduced the increase in
renin release after pretreatment with furosemide (142).
Similar results were obtained in vivo, where renin secretion was reduced in response to loop diuretics under
concomitant NOS inhibition (61, 722, 768). The interpretation of the results derived from studies with a pharmacological inhibition of NOS is complicated because it is
unclear to what extent the agents specifically inhibit each
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of the three NOS isoforms. In particular, the specificity of
the widely used agent 7-NI for nNOS over eNOS and
inducible NOS (iNOS) is based on its preferential in vivo
uptake by neuronal cells compared with endothelial cells,
rendering its specificity for nNOS in cells other than neurons questionable (597). To circumvent these issues and
to assess whether MD-derived NO is a functional stimulatory mediator of renin release in response to changes in
the tubular salt content, the effect of a loop diuretic on
renin secretion was investigated in nNOS- and eNOSdeficient mice (130). The loss of either nNOS or eNOS
activity had little impact on the magnitude of renin secretion in response to furosemide application. However, after the nonspecific inhibition of all NOS isoforms by NGnitro-L-arginine methyl ester (L-NAME), the furosemideinduced renin secretion was substantially reduced in
wild-type, nNOS ⫺/⫺, and eNOS ⫺/⫺ mice. These data
suggest that NO acts as an enhancer of renin secretion
irrespective of its source, and therefore, NO is not required to mediate the MD control of renin secretion.
Similarly, in the isolated perfused kidney, the effect of
bumetanide on renin secretion was blunted by NOS inhibition. However, clamping the NO concentrations in the
isolated perfused kidney by exogenous NO administration
with the concomitant inhibition of all NOS isoforms fully
restored the renin secretory responsiveness to bumetanide, suggesting again that the mere presence of NO is
sufficient and that a fluctuation in NO concentrations is
not required for the activation of the MD control of renin
secretion (130).
In summary, NO is generated in the vicinity of the JG
granular cells by nNOS and eNOS and serves as a stimulatory, permissive factor in renin secretion. On the basis
of the present data, it seems unlikely that NO derived
from MD cells functions as a mediator of the tubular
control of renin secretion.
3. Adenosine/ATP
Adenosine meets the key requirements to serve as a
mediator of the local tubular control of the renin system.
First, there is solid evidence that adenosine is generated
in the JGA. Second, the formation of adenosine in the JGA
depends on the tubular salt concentration in the MD
segment of the TAL. Third, adenosine exerts a direct
effect on renin secretion from JG granular cells of the
afferent arteriole.
A) TUBULAR NACL CONCENTRATION AND ADENOSINE FORMATION
IN THE JGA.
The function of adenosine as a paracrine factor
in the JGA has been the subject of intense research over
the past several years. The focus, however, has been on
the role of adenosine in the MD control of preglomerular
resistance (the so-called tubuloglomerular feedback
mechanism; Ref. 874) rather than its function in the local
tubular control of renin secretion. Nevertheless, progress
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made towards the elucidation of the signaling pathways
that connect the tubular MD cells with the vascular
smooth muscle cells of the afferent arteriole also expanded our knowledge of the local tubular control of
renin secretion. The data indicate that the following chain
of events is initiated by an increase in the tubular salt
concentration at the macula densa. First, MD cells detect
increases in the tubular NaCl concentration via enhanced
NKCC2-dependent NaCl reabsorption, the MD cells subsequently release ATP via their basolateral membrane,
and the ATP is successively dephosphorylated in the extracellular space to eventually form adenosine, which in
turn causes afferent arteriolar vasoconstriction and a concomitant drop in the GFR of the respective nephron (66,
90, 125, 455, 650, 832). A1 adenosine receptors (A1AR) are
expressed in vascular smooth muscle cells of the afferent
arteriole, with particularly high expression levels in the
most distal portion of the vessel (390), and they mediate
the vasoconstriction through the Gi-dependent activation
of phospholipase C (308). Since the granular JG cells also
express A1AR (11), it is conceivable that adenosine may
also influence or suppress renin secretion in response to
increases in the tubular NaCl concentration. In fact, the
dose-dependent inhibition of renin secretion by adenosine was demonstrated for isolated JG cells and renal
cortical slices (160, 474). The A1AR antagonists such as
8-cyclopentyl-1,3 dipropylxanthine (DPCPX) in turn result
in a stimulation of renin secretion, suggesting that the
renin system is tonically suppressed by endogenous adenosine formation (388, 469, 470). The assumptions that
renin secretion is controlled by an endogenous “adenosine-brake” (388) and that adenosine in this context is
derived from tubular sources, i.e., tubular ATP, are further supported by the observation that renin secretion in
the isolated JGA is lower in the presence of the tubular
MD segment than in its absence. This difference in the
renin release rate was eliminated by the nonspecific adenosine receptor antagonist theophylline (381). Similarly,
the PRA was increased in humans after the application of
the A1AR antagonist FK-453, again suggesting a tonic
inhibition of renin release by adenosine (43). The involvement of adenosine in the mediation of the MD-dependent
suppression of renin secretion in response to high tubular
NaCl was first suggested by in vitro experiments using the
isolated TAL/JGA preparation. In this experimental setup,
as mentioned above, an increase in the salt concentration
of the tubular perfusion fluid resulted in a reduction of the
renin release rate (815). The application of DPCPX to the
bath markedly reduced the magnitude of this decrease in
renin secretion, indicating that the activation of A1AR by
adenosine constitutes a crucial step in the signaling cascade between tubular cells and the effector cells of the
afferent arteriole (943).
The in vivo significance of adenosine in the tubular
control of renin secretion was assessed in studies using
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A1AR-deficient mice (90, 832). The effects of acute
changes in the tubular salt concentration were investigated in these mice by acute salt loading to raise the NaCl
concentration at the MD or by the application of loop
diuretics to mimic a low tubular salt concentration. The
acute salt loading was achieved by the intravenous application of isotonic saline, an experimental maneuver that
has been shown to result in increased distal tubular salt
concentration and a concomitant suppression of renin
secretion (440, 537). In A1AR ⫺/⫺ mice, the acute suppression of renin secretion provoked by acute salt loading
was completely absent, whereas the PRC was reduced in
wild-type controls by ⬃40% (436). The converse of salt
loading, a blockade of the MD salt transport by the use of
furosemide, resulted in a comparable stimulation of renin
secretion in both wild-type and A1AR-deficient mice, suggesting that the adenosine-dependent signaling is responsible for the inhibitory arm of the tubular control of the
renin system (436). In contrast to acute changes in the
tubular salt, the chronic modulation of oral salt intake does
not appear to be dependent on intact adenosine signaling.
Thus the stimulation and suppression of the renin system
under dietary salt-deprived conditions were fully preserved
in the A1AR ⫺/⫺ mice (784).
The assumption that this adenosine-dependent suppression of renin secretion derives from the tubular control of the renin system is further supported by the observation that the acute suppression of renin secretion
due to salt loading is also absent in NKCC2A-deficient
mice, a strain that lacks the isoform of NKCC2 responsible for MD salt-sensing in the high concentration range
(651, 652). However, both these and the A1AR-deficient
mice display a reduction in the PRC after chronic high salt
intake, similar to that observed in wild-type controls.
Thus A1AR- and NKCC2A-deficient mice maintain an inverse regulation of PRC after a high-salt diet, but they
have lost the ability to suppress PRC after acute salt
loading (652). Since NKCC2 expression is restricted to the
TAL (211, 640, 970), these data again suggest that the
negative tubular control of renin secretion is more relevant for acute changes in tubular NaCl than for chronic
changes and that a lack of tubular control can be compensated for by other factors when salt intake is chronically increased.
B) ADENOSINE AND PRESSURE-DEPENDENT REGULATION OF RENIN SECRETION. With respect to the pressure-dependent control of renin secretion, the contributions of local tubular,
vascular, and systemic factors remain to be determined
(see also sect. IVB). The experimental evidence suggests a
crucial role for the adenosine-dependent signaling in the
tubular domain. Thus the acute and chronic phenylephrine infusion in vivo resulted in a suppression of PRC in
wild-type mice, but not in A1AR-deficient mice, despite
similar increases in the arterial pressure (783). Similarly,
in the isolated perfused kidney, the A1AR deficiency and
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inhibition of A1AR by DPCPX eliminated the suppression
of renin secretion in response to a stepwise increase in
the renal perfusion pressure (783). Conversely, renin secretion was enhanced by a decrease in the perfusion
pressure, irrespective of whether functional A1AR was
present or not (783). The results of this in vitro study
resemble an in vivo experiment in which the vasodilator
agent hydralazine was used to reduce the arterial pressure. Again, PRC was enhanced to a similar extent after
hydralazine administration in A1AR ⫺/⫺ mice and wildtype controls (436). These data suggest that intact adenosine signaling is critical to the pressure-dependent inhibitory arm of renin secretion, whereas other factors (rather
than decreased adenosine formation) appear to be responsible for the stimulatory arm, which is activated by
low arterial pressure.
B. Vascular Control of Renin Secretion
JG granular cells in the afferent arteriole are surrounded and influenced by neighboring vascular smooth
muscle cells and endothelial cells (see also sect. IIIC).
Multiple local factors derived from the vasculature may
influence renin expression and secretion, as summarized
in detail elsewhere (293). We focus on four major local
factors that appear to be primarily involved in the communication among vascular smooth muscle cells, endothelial cells, and JG cells: NO, adenosine/ATP, endothelins, and prostanoids. In this section, we also assess the
data that relate to the regulation of renin secretion by the
local “baroreceptor,” although it is still difficult to define
whether and to what degree the local baroreceptor is
related to vascular or tubular events or events that occur
within JG cells.
1. NO
Due to the expression of eNOS, the endothelium is a
rich source of NO in most vascular beds, including the
kidney. Specifically, the expression of eNOS in the afferent arteriole has been shown for a number of mammalian
species (40, 41, 896). A coculture of JG cells with endothelial cells revealed both inhibitory and stimulatory signaling derived from the endothelial cells, with the stimulatory component related to endothelium-dependent NO
formation (462, 481, 773). In contrast, the NOS inhibition
in the absence of endothelial cells had no effect on the
renin secretion from JG cells, presumably due to the lack
of NOS expression in JG cells (773). The relevance of
endothelium-derived NO for the release of renin was further supported by studies in the isolated perfused kidney.
The addition of acetylcholine, a known stimulator of endothelial NO release (248), to the perfusion fluid increased the renin release rate, which was blunted by a
concomitant NOS inhibition (610, 765). Furthermore,
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eNOS was shown to have a considerable tonic stimulatory
influence on renin transcription in vivo without being
involved in the regulation of renin mRNA expression under conditions such as a high-salt or low-salt diet in
combination with the ACE inhibitor ramipril (923). Finally, as mentioned above, in vivo data from eNOS- and
nNOS-deficient mice suggest that the adequate NO generation in the vicinity of JG cells, irrespective of whether
the source is endothelial (eNOS) or tubular (nNOS), constitutes a permissive factor that allows other regulatory
mechanisms of PRC to operate at full magnitude (130).
2. Adenosine/ATP
The function of adenosine in the local control of
renin secretion was touched upon in connection with the
tubular mechanisms that account for the adenosine-dependent suppression of renin secretion. The formation of
adenosine in the confines of the JGA, however, is not
limited to the ATP release by MD cells and the subsequent
extracellular dephosphorylation resulting in the formation of adenosine (66, 455). ATP is also known to be
released by endothelial cells and vascular smooth muscle
cells, e.g., in response to increased shear stress (80, 582,
678, 786, 938). In fact, the renal extracellular ATP concentration as determined by microdialysis has been shown to
be directly related to the renal perfusion pressure, which
was most likely related to both tubular and vascular ATP
release (631, 632). Of note, some regulatory capacity of
renin secretion by the renal perfusion pressure was preserved in hydronephrotic kidneys, i.e., in the absence of
functional tubular-JG signaling (766). Thus the vasculature-dependent ATP release plays a key role in mediating
the renal autoregulation in response to increased perfusion pressure (375, 376, 554). In addition, JG cells were
shown to release ATP in response to mechanical stretching (973); in this context, ATP could subsequently either
influence JG cells in an autocrine manner, or ATP might
be subject to dephosphorylation in the extracellular
space. In terms of an increased renal perfusion pressure,
the overall effect of ATP released by the endothelial,
smooth muscle, or JG cells is supposedly the suppression
of renin secretion (973). Since ATP, however, has been
shown to stimulate renin secretion from renal cortical
slices, presumably via enhancing endothelial NO generation (162), it is likely that the bulk of the ATP present
in vivo is locally hydrolyzed to form adenosine, which
then acts on A1AR (160, 474), or that the ATP acts directly
on the P2 purinoreceptors present on JG cells (973).
In summary, the vascular release of ATP and subsequent formation of adenosine in the extracellular space
appears to contribute to the local adenosine formation,
which results in a suppression of renin secretion mediated by the activation of A1AR. This may be of particular
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relevance during situations of increased renal perfusion
pressure.
3. Adenosine/ATP and renal baroreceptor
The term renal baroreceptor describes the inverse
relationship between the intrarenal (perfusion) pressure
and renin secretion. Although it is still difficult to pinpoint
the exact nature of the renal baroreceptor, it appears
likely that the adenosine/ATP from vascular and tubular
sources is crucially involved in the suppression of renin
secretion during increased intrarenal pressure, as mentioned above. In addition, mechanical stretching results in
the release of ATP from JG cells (973). This release of
ATP from JG cells may provide a tubule-independent link
between renal perfusion pressure and renin secretion and
may participate in the still elusive local “baroreceptor.”
Multiple studies describe a stretch or transmural pressure
dependency of JG function. Thus in isolated JG cells, the
mechanical stretch reduces both the basal and prestimulated renin secretion in parallel with reduced renin transcription (117). In addition, the processing of pro-renin
into active renin is attenuated by transmural pressure on
JG cells (339). Similar results were obtained for the reninexpressing cell line As4.1 after mechanical elongation
(736). In this study, the activity of a renin promoter reporter construct was diminished upon mechanical
stretching. The mechanical stretching of the As4.1 cells
also induced a rise in the intracellular calcium, the wellestablished intracellular inhibitor of renin formation (see
sect. IIID) (738). Contrary to this report, however, the
mechanical stretch of mouse JG cells in situ in isolated
afferent arterioles did not affect the JG cell calcium levels
(761).
In summary, the investigation into the mechanisms
underlying the local renal baroreceptor and the pressuredependent control of the renin system requires further
experimental efforts. It appears most likely that the
baroreceptor is composed of several factors, including
tubular, vascular, and JG cell-related components.
4. Endothelins
Multiple studies have suggested that endothelins
serve as negative regulators of renin expression and secretion. A primary culture of JG cells revealed that endothelin-1, -2, and -3 all inhibit the increase in renin secretion that occurs after the stimulation of the cAMP pathway, whereas they have little influence on the baseline
renin secretion. The in vitro effect of endothelins on the
cAMP-stimulated renin secretion was not modulated by
the ETA receptor antagonist BQ123. Conversely, the ETB
agonists like IRL-1620 and sarafotoxin S6b had similar
effects on the renin secretion as those elicited by endothelins, suggesting that the endothelins influence renin
secretion via activation of the ETB receptors (4, 728).
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Similar results were obtained with regard to renin gene
expression (727). For the isolated perfused kidney, a
slight increase in the renin release rate was observed at a
low endothelin concentration (10 pM), whereas higher
concentrations consistently suppressed renin secretion;
once again, this effect was primarily mediated by ETB
receptors (763). It is conceivable that the activation of the
ETB receptors exerts a dual effect on renin secretion, with
a stimulatory component related to the enhanced endothelial NO formation (218, 337) and a direct inhibitory
component that depends on the ETB receptors present on
JG cells. The correlation between endothelins and the
renin system in vivo was assessed during chronic hypoxia
in rats (782). The ET receptor antagonist LU135252 administered during chronic hypoxia resulted in a marked
increase in renin gene expression, suggesting a negative
effect of endothelins on the renin system and basically
confirming the in vitro data (782).
At present, our knowledge of the functional impact
and relevance of the endothelin system on the regulation
of renin expression and secretion is limited. Endothelins
apparently act as endothelial factors that tonically counteract the stimulatory effects of other endothelium-derived factors, most notably NO. Since the endothelial
generation of endothelin-1, in particular, was shown to be
related to vascular shear stress (733), it appears reasonable to suggest an involvement of the endothelin system
in the pressure-dependent regulation of renin secretion, a
possibility that awaits further experimental evaluation.
5. Prostanoids
The role of prostanoids in the control of renin expression and secretion was discussed in detail in the
context of tubular prostanoid formation. However, in addition to the tubules, the renal vasculature also appears to
be a significant source of prostanoids, particularly prostacyclin. In humans, the substantial expression of COX-2
was observed in the afferent arteriole in close vicinity to
the granular JG cells, which exceeded the expression of
COX-2 in the TAL (867). In rodents, conversely, no COX-2
but some COX-1 was found in the renal vasculature (113).
The vascular expression of COX-2 in humans was enhanced in patients with renal artery stenosis, and therefore, vascular COX-2 activity may contribute to the increased renin generation during renal hypoperfusion.
Similarly, in mice, the formation of prostacyclin and the
activation of the IP receptors appear to be crucial for the
activation of renin secretion during renal hypoperfusion.
Accordingly, the stimulation of the renin system during
renal artery stenosis was markedly reduced in IP receptordeficient mice (244). In addition, stimulation of the renin
system after the application of loop diuretics may be at least
partly related to the enhanced vascular prostacyclin formation (518). Conversely, the attenuation of renin secretion in
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response to loop diuretics by inhibitors of cyclooxygenases
appears to be partially mediated by the reduced vascular
prostacylin synthesis (344, 414, 415, 827).
In conclusion, prostanoids derived from vascular
sources in the vicinity of JG cells (or from the systemic
vasculature, as outlined in section V) constitute potent
stimulators of renin secretion and expression. Their contribution to overall prostanoid formation may be considerably species dependent. Changes in the formation of
prostanoids, e.g., in response to decreased renal perfusion pressure, are not restricted to changes in the tubular
prostanoid formation, but they are often paralleled by
regulated vascular prostanoid formation.
C. Neural Control of Renin Secretion
The presence of ␤1-adrenergic receptors in the JG
granular cells has been established by multiple receptor
binding studies and by in situ hybridization. The results of
these investigations are summarized in detail elsewhere
(293). More recently, the expression of ␤1-receptors on JG
cells was shown by immunohistochemistry (81). The activation of ␤1-receptors by catecholamines results in an
augmented formation of cAMP, the central intracellular
stimulus of renin secretion (see sect. III). Thus the pharmacological inhibition of ␤1-receptors results in reduced
renin secretion (130, 423). Similarly, renal denervation to
excise sympathetic input was shown to lower renin expression (271, 354), but it should be noted that renal
denervation also removes the input of the sympathetic
system mediated by ␣-receptors, including hemodynamic
and tubular effects (335). Most notably, double-knockout
mice deficient in ␤1- and ␤2-receptors have substantially
reduced basal PRC, ⬃85% lower than that observed in
wild-type controls (434). Thus the sympathetic input from
local nerve endings or from circulating catecholamines
may represent the most powerful background stimulus
for renin secretion. In view of the significance of the
sympathetic nerve tone for the maintenance of basal renin
secretion, it appears reasonable to also suggest an involvement of sympathetic input in the regulation of renin
secretion triggered by changes in oral salt intake. It
should be mentioned in this context that the renal sympathetic nerve activity is higher in rats on a low-salt diet
than in those on a high-salt diet (118). However, most
studies suggest that modulation of the activity of the renin
system is not crucially dependent on intact ␤-adrenergic
input. That is, most reports indicate that neither renal
denervation nor pharmacological ␤-blockade considerably influence the stimulation of the renin system by a
salt-deficient diet or its suppression by a high-salt diet
(271, 353, 354). In some studies in humans, dogs, and rats,
however, the ␤-receptor antagonist propranolol was
shown to reduce the magnitude of the renin system stimPhysiol Rev • VOL
ulation during a salt-deprived diet (423, 879). These somewhat contradictory results might be attributed to differences in the species or in the specific experimental setups
used. However, for most in vivo studies utilizing ␤-antagonists, it has remained unclear to what extent ␤-inhibition
was achieved. Those issues were circumvented by the use
of ␤1/␤2 double-knockout mice (434). As mentioned
above, basal renin expression and PRC in ␤1/␤2 ⫺/⫺ mice
were both substantially reduced compared with wild-type
controls. In ␤1/␤2 ⫺/⫺ mice, the changes in renin secretion that occurred in response to both acute and chronic
stimuli, such as oral salt intake, loop diuretics, ACE
blockers, and AT receptor antagonists, were maintained;
however, the magnitudes of these changes in the PRC
were markedly diminished (434).
In summary, activation of JG cell ␤1 receptors is
required to sustain basal renin expression and secretion.
Furthermore, the ␤1 receptors are necessary to drive the
renin synthesis needed to maintain a releasable renin
pool, which provides the basis for the full-magnitude
secretory responses to external stimuli.
V. SYSTEMIC CONTROL OF RENIN SYNTHESIS
AND SECRETION
The RAAS is critically involved in the regulation of salt
and volume homeostasis and in the control of blood pressure. These variables in turn influence renin synthesis and
renin release via negative-feedback loops. In addition, renin
synthesis and release are also influenced by sympathetic
nerves, tubular mechanisms, renal autacoids, and hormones.
We discuss, in this section, the newest advances relevant to
the regulation of renin release and synthesis.
A. Blood Pressure
The regulation of blood pressure involves a variety of
organ systems including the central nervous system (CNS),
cardiovascular system, kidney, and adrenal glands. These
systems modulate cardiac output, fluid volume, and peripheral vascular resistance as the major determinants of blood
pressure. The renin-angiotensin system is a key regulator of
blood pressure and salt and water homeostasis (946). The
inhibitors of ACE or ANG II receptor antagonists are
potent blood pressure-lowering drugs that may also attenuate cardiovascular and renal injuries (945, 954). Due to
changes in the formation of the vasoconstrictor ANG II,
alterations in renin release can also cause changes in the
arterial blood pressure, such that an increased rate of
renin release increases blood pressure and vice versa.
Accordingly, renin inhibitors have been shown to lower
blood pressure to similar levels as ANG II-AT1 receptor
blockers or ACE inhibitors (544). Furthermore, mice with
genetic deletions of angiotensinogen, renin, ACE, and
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AT1a receptors (in contrast to humans and all other mammalian species, rodents posses two AT1-receptor isoforms: AT1a and AT1b) are hypotensive (220, 380, 432, 466,
967). Virtually all tissues presumed to have a major role in
blood pressure control, including the heart, the vasculature, the adrenal glands, the nervous system, and the
kidney, express AT1 receptors (164). Via activation of the
AT1 receptors, ANG II triggers multiple effects, such as
vasoconstriction, stimulation of aldosterone release, central vasopressor responses, and increased renal sodium
retention (8, 30, 182, 230, 877), which may potentially lead
to an increase in the systemic blood pressure. It has been
assumed that the body has several important systems for
controlling blood pressure, which react within seconds
(baroreceptors, chemoreceptors, and CNS ischemic response), minutes (the RAAS, stress relaxation, capillary
fluid shift, and aldosterone release), and finally hours or
days (renal volume control) (291). Nevertheless, it has
been suggested that the kidney is the dominant mechanism for the long-term regulation of blood pressure; as
such, an elevation in the renal perfusion pressure due to
an increased arterial blood pressure enhances sodium
and water excretion, leading to a decrease in body fluid
volume and vice versa (“pressure natriuresis”) (291).
Moreover, renal transplantation studies further support
the central role of the kidney in regulating blood pressure
(725). The RAAS modulates renal function such that the
activation of the RAAS causes a shift of the pressurenatriuresis curve to the right and the inhibition of the
RAAS causes a shift to the left. This was demonstrated,
for example, by showing that the infusion of ANG II into
the renal artery reduced the sodium reabsorption and
increased blood pressure without impairing peripheral
resistance (300, 302). A critical role for renal AT1a receptors derives from the AT1a receptor-deficient mice, which
develop a salt-sensitive hypertension (646). Recently, renal cross-transplantation studies with AT1a receptor-deficient mice and wild-type mice further demonstrated the
importance of renal AT1a receptors for blood pressure
control. The specific absence of renal AT1a receptors
(“renal knockout”) lowered blood pressure from ⬃118
mmHg in wild-type mice to 99 mmHg in renal knockouts,
suggesting that the kidney is an important determinant of
blood pressure control (173). However, there is also evidence of a role for the RAS in the control of blood
pressure in nonrenal tissues. In this context, it has been
found, for example, that the injection of ANG II into the
brain increases blood pressure, likely via activation of the
AT1a receptors (15, 182), and that the systemic infusion of
ANG II induces vasoconstriction via the activation of
vascular AT1a receptors. To address the role of extrarenal
tissues in the control of blood pressure, Crowley et al.
(173) also investigated a “systemic AT1a-receptor knockout” with intact renal AT1a receptors; they found that
blood pressure decreased to the same extent as for renal
Physiol Rev • VOL
631
knockouts. Because blood pressure was further reduced
to ⬃86 mmHg in animals that completely lacked the AT1a
receptors, these findings suggest that both renal and extrarenal AT1a receptors contribute to blood pressure control (173). Subsequently, the authors showed that ANG
II-induced hypertension depends on the presence of intact renal AT1a (172).
As part of a negative-feedback loop, blood pressure
in turn affects the synthesis and release of renin from the
JG cells of the kidney: an increase in the arterial blood
pressure inhibits, whereas a decrease stimulates, the synthesis and secretion of renin (925). This pressure-dependent mechanism, which controls renin synthesis and release, was denoted the “long negative-feedback loop”
(293). Increases in the systemic blood pressure can inhibit
renin release via intrarenal as well as extrarenal mechanisms. Both mechanisms have been suggested to be involved in the pressure-dependent regulation of the renin
system. With regard to intrarenal mechanisms, high blood
pressure 1) induces pressure-dependent natriuresis,
which increases the NaCl load at the macula densa, and
2) increases the renal perfusion pressure and therefore
influences the renal baroreceptor mechanism.
Since the effects of blood pressure on renin secretion
also occur in the isolated kidney (765), it seems likely that
the renal baroreceptor mechanism could be involved in
the pressure-dependent regulation of renin release. Although the precise identity and localization of the renal
baroreceptor are still unclear, this sensing “receptor” may
be located within the afferent arteriole. Much effort has
been spent in attempting to discriminate between the
pressure-dependent effects and the MD mechanism. However, the baroreceptor response was shown to be independent of the tubular (MD-mediated) effects (293), although the MD may still participate in the pressure-dependent effects (766, 767). In addition, it has been shown
that the renal perfusion pressure, not the renal perfusion
flow, is important for renin secretion (617). As outlined
before, several renal autacoids have been shown to modulate the pressure-dependent regulation of the renin system, with roles for NO and prostaglandins in response to
a drop in the renal perfusion pressure and for adenosine
in response to an increased arterial blood pressure (see
sect. IVB for details). The renal cross-transplantation studies with AT1a receptor-deficient mice may also provide
further insight into the regulation of renin by the renal
baroreceptor mechanism. The renal AT1a-receptor knockouts had normal renin mRNA levels, despite the absence
of AT1a receptors at the JG cells and a significantly lower
blood pressure, two factors that have been suggested to
increase renin synthesis and renin release. However, renin strongly increased in the complete knockouts, which
was paralleled by a further decrease in blood pressure
(173). Therefore, one may assume that the renal baroreceptor mechanism may be primarily responsible for the
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CASTROP ET AL.
strong rise in renin mRNA in the total AT1a-receptor
knockouts. Because blood pressure reductions of ⬃20
mmHg did not increase renin mRNA, these data further
suggest that a threshold of blood pressure lowering must
be achieved to stimulate the renin system via the renal
baroreceptor mechanism, as was anticipated in earlier
studies (439).
An important extrarenal mechanism involved in the
control of renin secretion is the renal sympathetic nerve
activity (RSNA). The autonomic nervous system, via the
renal sympathetic nerves, adjusts kidney function dynamically in response to changes in the sensory information
arising from the cardiovascular system, the soma, viscera,
and the higher cortical centers. The renal sympathetic
nerves innervate the vascular and tubular components,
thereby regulating the renal hemodynamics, salt and water reabsorption, and renin secretion (868). The kidney
has dense sympathetic innervations of vascular smooth
muscle cells of the afferent and efferent arterioles, including the JG cells, as well as of most of the tubular segments
in the cortex, including the proximal tubule, the loop of
Henle, and the distal tubule (46, 194). Increases in the
RSNA increase renin secretion, decrease urinary sodium
excretion, and decrease the renal blood flow and GFR
(194, 511, 557). With the use of graded frequency renal
sympathetic nerve stimulation, it was found that the frequency response curve for renin secretion was to the left
of that for decreases in sodium excretion, which, in turn,
was to the left of that for decreases in renal blood flow.
Therefore, it was assumed that an increase in renin secretion could be achieved before antinatriuresis and renal
vasoconstriction occurs (194, 406). However, a resulting
increase in ANG II due to the increased release of renin by
the low levels of renal nerve activation could itself affect
urinary excretion. In a recent study, it was shown that a
low-level stimulation of renal nerves resulted in an ANG
II-dependent increase in blood pressure and a decrease in
the renal blood flow, urine flow rate, and sodium excretion, which was attenuated by ACE inhibition. Therefore,
these data suggest that the changes in urinary excretion in
response to activation of the renal nerves are mediated
directly by the renal nerves and indirectly by an increase
in ANG II, which may be due to an increase in renin
secretion (502).
Afferent inputs to the CNS from the somatosensory
receptors, cardiovascular baroreceptors, visceral receptors, renorenal reflexes, and higher cortical centers modulate the RSNA. Cardiovascular baroreceptors have been
suggested to be of major importance for afferent inputs.
The deactivation of high pressure receptors of the carotid
sinus and the aortic arch led to an increase in the RSNA
in response to a fall in blood pressure (119), and the low
pressure receptors of the cardiopulmonary area inhibit
the RSNA in response to an increase in volume within the
vascular system (196). It is well known that stimulation of
Physiol Rev • VOL
the left atrial receptors leads to a reflex reduction in the
RSNA and the inhibition of renin release (298), and a fall
in the systemic blood pressure unloads the carotid baroreceptors and leads to the stimulation of renin release (195,
868). However, the increased renin secretion in response
to hypotensive hypovolemia does not seem to depend on
the cardiac or arterial baroreceptors (704, 872, 873, 932).
The arterial baroreceptors have long been considered to be only crucial for the short-term control of blood
pressure (169, 869). However, in a new model of chronic
baroreceptor unloading, it has been found that blood
pressure, heart rate, and plasma renin activity increase in
response to baroreceptor unloading, suggesting that arterial baroreceptors are also involved in the long-term control of blood pressure (870, 871). Additional supporting
evidence derives from the studies of Lohmeier et al. (527),
who investigated the responses to five days of ANG II
infusion in dogs using a split-bladder preparation combined with the denervation of one kidney. During ANG II
infusion, the sodium excretion from the innervated kidney increased compared with the denervated kidney, indicating a chronic decrease in the RSNA in response to
ANG II. This effect seemed to be mediated by the baroreflexes. In a subsequent study, they found an increase in
sodium excretion in the innervated kidney in response to
chronic ANG II infusion (528). Similarly, it has been found
that the decrease in RSNA in response to chronic infusion
of ANG II in rabbits is baroreceptor mediated (48, 49).
Thus these data further support the role of arterial baroreceptors in the long-term regulation of blood pressure.
Moreover, these results suggest that the baroreflexes may
actually inhibit the renal sympathetic nerve during ANG
II-induced hypertension, and in the absence of these reflexes, ANG II has sustained renal sympathoexcitatory
effects. Accordingly, it has been found that the chronic
activation of the carotid baroreflex reduces blood pressure, heart rate, and plasma norepinehrine levels. However, the plasma renin activity was unchanged, despite a
strong fall in blood pressure, suggesting the presence of
an inhibitory influence, likely baroreflex-mediated renal
sympathoinhibition, on the renin release during sustained
activation of the carotid baroreflex (526). This assumption is supported by acute observations in chronically
instrumented dogs (686). Surprisingly, bilateral renal denervation had no impact on the blood pressure response
and on renin secretion following prolonged baroreflex
activation (524). Therefore, the presence of renal nerves
does not seem to be an obligate requirement for long-term
reductions in the arterial pressure and renin release during prolonged activation of the baroreflex.
Furthermore, the renal nerve activity, as well as arterial baroreflex control, can be modulated by ANG II
within the CNS (193, 338, 566, 741). In addition, several
other sensory receptors, including nociceptors, metabo-,
mechano-, osmo-, chemo-, and thermoreceptors, can in-
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PHYSIOLOGY OF KIDNEY RENIN
fluence the level of sympathetic nerve activity and, consequently, the renin release and synthesis (195, 461).
In summary, blood pressure is an important regulator
of renin release and synthesis. The blood pressure-dependent renin release is influenced by the activity of the renal
nerves, by baroreceptor reflex loops and renal perfusion
pressure, which in turn control the renin release via the
intrarenal baroreceptor mechanism.
B. Salt Intake
Oral salt intake is a well-known important regulator
of RAAS activity, such that low salt intake increases and
high salt intake decreases renin synthesis and secretion
(925). Recently, it was found that sodium intake determines the activity of the renin system in a log-linear
fashion (441). The salt-dependent changes in the RAAS
activity have been suggested to be mediated by 1) systemic humoral factors, 2) intrarenal factors, 3) renal
nerves, or 4) the intrarenal MD mechanism. At present,
however, it is still unclear which factor(s) or mechanism(s) mediates the observed salt-induced changes.
The role of local factors, including the intrarenal MD
mechanism, locally acting mediators, and renal nerves, in
the salt-induced changes in the renin system was discussed above in detail. As outlined there, the MD-dependent (tubular) control of renin secretion in response to
changes in the luminal NaCl concentration seems to be
more relevant for acute than for chronic changes in the
tubular NaCl. Furthermore, locally generated mediators
like the COX-2-derived prostanoids and NO act as modulators of the RAAS activity rather than as major mediators
of the long-term salt-dependent control of the renin system (see sect. IVA). Several studies have indicated a suppression of the sympathetic nervous system with high salt
intake (25, 196, 525). Therefore, the inhibition of the RAS
in response to high salt intake may be due to a reduction
of the RSNA. More recently, however, it has been found
that a high-salt diet decreased the PRA independent of
RSNA in rabbits (570, 571). Therefore, the renal nerve
activity seems to serve as a stimulator of the renin system
but not as a mediator of the control of the renin system by
salt (see sect. IVC).
Arguments against an intrarenal mechanism, especially in long-term control of the renin system by salt
intake, derive from the following: 1) findings in nonfiltrating kidneys, in which the regulation of the renin system by
salt intake is unaltered, although the MD mechanism is
obviously not intact (50, 777, 986), and 2) results from
mice with a genetic deletion of NKCC2A, where the longterm regulation of renin secretion by salt intake was not
altered, although the suppression of renin secretion in
response to acute salt loading was absent (652). Since this
dissociation between acute and chronic regulation of the
Physiol Rev • VOL
633
activity of the renin system in response to salt intake is
also seen in A1 adenosine receptor-deficient mice (91,
436, 784), one may conclude that intrarenal factors, especially the MD mechanism, are not essential for the chronic
control of the renin system by salt intake. Instead, extrarenal-derived factors are likely to be critically important.
Changes in salt intake may lead to changes in systemic blood pressure in some individuals, such that high
salt intake can increase and a low salt intake can decrease
blood pressure (637). Because changes in blood pressure
also lead to changes in the activity of the RAAS, it might
therefore be plausible that the salt-induced changes in
renin expression and secretion are due to changes in
systemic blood pressure. However, there is evidence of
blood pressure-independent natriuresis and regulation of
the renin system (21–24, 353, 746, 747). It has been found
that acute salt loading, either by isotonic or hypertonic
solutions, was followed by natriuresis without changes in
blood pressure, and in one study, this effect even occurred together with a fall in blood pressure (22). These
findings suggest that the response to sodium load may
take place in the absence of increases in blood pressure,
and therefore, the pressure-natriuresis concept may be
inadequate (75). In addition, it was shown that the natriuresis in response to sodium load, which increased blood
pressure, was inhibited by the administration of ANG II,
suggesting that a decrease in the RAS is a prerequisite for
the natriuretic response to sodium load (21, 74). Subsequent elegant studies in humans and laboratory animals
further suggest that the suppression of renin release in
response to an acute modest sodium load is not only
independent of changes in blood pressure, but also independent of cardiac output, GFR, ANP, ␤1-adrenergic receptors, plasma sodium levels, osmolality, renal nerves,
and nNOS-derived NO (73, 456, 593, 717). Therefore, the
question arises which mechanism(s) mediates natriuresis
and suppression of renin in response to an acute modest
sodium load. It seems likely that the MD mechanism is a
major determinant of the renin release in response to an
acute modest sodium load. Apart from the MD mechanism, a currently unknown mediator may be involved in
the salt-induced changes of the renin system.
Taken together, sodium balance is an important regulatory mechanism for the activity of the renin system. It
is currently unclear which mechanism or mediator is
principally responsible for the salt-dependent regulation
of renin synthesis and release, especially during chronic
alterations in salt intake. The existence of such a humoral
factor remains elusive.
C. Hormones, Autacoids, and Other Mediators
A large variety of biological agents are known to influence renin synthesis and/or renin release. Many of these are
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CASTROP ET AL.
of major relevance, and an established role in renin synthesis and/or secretion has been demonstrated; conversely, for
others, there is only evidence on the cellular or isolated
organ level or when given exogenously. These biological
agents include classical hormones, autacoids, vitamins, cytokines, or the metabolite succinate (see Table 2). The role
of cytokines and vitamins is described in section II, and the
TABLE
2.
role of rather locally acting mediators, such as adenosine,
norepinephrine, NO, endothelins, and prostanoids, has been
described in section IV. In addition, the review by Hackenthal
et al. (293) provides a detailed overview about the influence
of angiotensin, antidiuretic hormone (vasopressin), prostaglandins and leukotrienes, dopamine, ANP, kallikrein and
kinins, vasoactive intestinal polypeptide, histamine, platelet-
Signal molecules
Substance
Cellular Effect
12-Hydroxyeicosatetraenoic acid
Not determined
Acetylcholine
Not determined
Adenosine
Inhibition
Adrenomedullin
Aldosterone
Angiotensin II
Atrial natriuretic peptide
Bradykinin, kinins
Calcitonin gene-related peptide
Catecholamines (␤1-adrenoreceptor)
Catecholamines (␣-adrenoreceptors)
Dopamine
Endothelins
Estrogens
Stimulation
Stimulation
Inhibition
Inhibition
Stimulation
Stimulation
Stimulation
Inhibition
Stimulation
Inhibition
No effect
Glucocorticoids
Growth hormone
Stimulation
No effect
Histamine
Insulin-like growth factor I
Stimulation
Not determined
Interleukin-1
Interleukin-6
Leptin
Inhibition
Inhibition
Not determined
Neuropeptide Y
Not determined
Nitric oxide
Stimulation
Oncostatin M
Oxytocin
Inhibition
Not determined
Pituitary adenylate cyclaseactivating polypeptide
Platelet activating factor
Progesterone
Stimulation
Prostaglandins (PGE2, PGI2)
Stimulation
Substance P
Succinate
Inhibition
Not determined
Testosterone
No effect
Thyroid hormone
Tumor necrosis factor-␣
Vasoactive intestinal polypeptide
Stimulation
Inhibition
Not determined
Vasopressin
Vitamin A
Vitamin D
Inhibition
Stimulation
Inhibition
Inhibition
Not determined
Physiological Function
Pharmacological tool; inhibition
using renal cortical slices
Pharmacological tool; no effect
using renal cortical slices
Mediator, modulator
Pharmacological tool
Pharmacological tool
Mediator, modulator
Pharmacological tool
Pharmacological tool
Pharmacological tool
Mediator, modulator
Pharmacological tool
Modulator
Pharmacological tool
Pharmacological tool; stimulation
in animal models
Pharmacological tool
Pharmacological tool; stimulation
in humans and rats
Pharmacological tool
Pharmacological tool; stimulation
in renal cortical slices
Pharmacological tool
Pharmacological tool
Pharmacological tool; no effect
after intra-arterial or
intravenous infusion
Pharmacological tool; no effect
using renal cortical slices;
inhibition in animal models
Modulator
Pharmacological tool
Pharmacological tool; stimulation
in animal models
Modulator
Pharmacological tool
Pharmacological tool; stimulation
in man
Modulator
Pharmacological tool
Modulator; stimulation in isolated
superfused glomeruli
Pharmacological tool; stimulation
in animal models
Pharmacological tool
Pharmacological tool
Pharmacological tool; stimulation
in isolated superfused
glomeruli
Modulator
Pharmacological tool
Modulator
Physiol Rev • VOL
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Reference Nos.
27
184
43, 90, 382, 436, 470, 474, 783, 784, 814,
832, 943
141, 247, 397, 496
444
99, 606, 647, 696, 775, 802, 904
102, 213, 331, 475, 639, 696, 743, 797, 913
62, 63, 696, 839-841
482
9, 235, 299, 354, 355, 434, 598
484, 567, 603, 816, 905
350, 373, 476, 535, 586, 963, 985
4, 609, 714, 727, 728, 737, 763, 782
89, 444, 550, 551
444
175, 347, 413, 588, 589, 959
260, 696, 709, 785
408, 563, 564
399, 522, 691
668
793, 914
10, 38, 77, 168, 221, 292, 798
60, 61, 130, 142, 326, 407, 477, 479, 481,
489, 683, 722, 765, 768, 770, 773, 923
52
360, 361, 530, 810
322
692
641, 642
240, 241, 244, 401, 435, 569, 635, 778,
901, 934
696
53, 324, 887, 908
45, 149, 217, 256, 444, 719
144, 145, 207, 320, 367, 445-447, 560
880, 884
109, 198, 697
28, 99, 278, 334, 485, 556, 759, 776, 902
796
516, 980
635
PHYSIOLOGY OF KIDNEY RENIN
activating factor, acetylcholine, calcitonin gene-related peptide, and endothelin in the release and synthesis of renin. If
new findings have since been reported, the role of these
mediators has been updated within this section. Otherwise, we refer readers to the review by Hackenthal et al.
(293). For an overview of the putative receptors on JG
cells, please see Table 3. It should be noted that Table 3
contains findings reported from cell cultures (As4.1 cells,
isolated JG cells, and human transfected JG cells) and from
histological approaches, which do not always definitively
allow the conclusion that a receptor is colocalized with the
native renin-producing JG cells.
1. ␤-Adrenergic pathway
It is well known that the sympathetic nervous system participates in the release of renin via the ␤-adrenergic pathway (293), as outlined in detail in section IVC.
JG cells contain ␤1-adrenergic receptors (81, 161). The
systemic application of the ␤-adrenoreceptor agonist
isoproterenol by chronic infusion into rats, both time
and dose dependently, stimulates the synthesis and
secretion of renin (355, 598, 802). In addition, isoproterenol infusion increased renin mRNA expression and
PRA in rats during normal and high salt intake, but not
during low salt intake (355). Notably, COX-2-derived prostanoids do not seem to be involved in the isoproterenolinduced stimulation of the renin system (435, 569).
TABLE
3.
In agreement with the stimulatory effects of the
␤-adrenoreceptor agonist isoproterenol on basal renin
secretion, chronic ␤-adrenoreceptor antagonism has
been found to decrease basal renin synthesis and secretion (354, 987). However, ␤-adrenoreceptor antagonism did not influence the increase in renin synthesis
and secretion due to low salt intake (987), ANG II type
1 receptor blockade (924), or the combination of low
salt intake with ACE inhibition (342), but it did attenuate the stimulation of the renin system in response to
chronic stress (9), acute angiotensin AT1 receptor
blockade (299, 662), and hypotensive hemorrhage
(354). Additionally, oxytocin-induced renin release
seems to be mediated via activation of the ␤-adrenergic
system (360), whereas thyroid hormone stimulates the
renin system independent of the sympathetic nervous
system (447).
In summary, the sympathetic nervous system provides one of the most powerful background stimuli for
renin synthesis and secretion. Its relevance as a regulatory factor of the renin system appears to be limited.
2. ANG II
Circulating ANG II functions in a direct negativefeedback loop (“short negative-feedback loop”) to inhibit
renin synthesis and secretion (293). Numerous in vivo
studies have shown that inhibiting the effects of ANG II
Expression of receptors on juxtaglomerular cells
Mediator
Adenosine
Aldosterone
Angiotensin II
ANP
Bradykinin
Calcium
Catecholamines
CGRP, ADM
Dopamine
Endothelin
EGF
Glucocorticoid
Histamine
Neuropeptide Y
Neutrophins
Oxysterols
Oxytocin
PACAP
PGE2
Prostacyclin
TGF-␤
Thyroid hormone
Vasopressin
Receptor
Species
Level of Evidence
A1
MR
AT1
AT2
NPR1
B2
CaR
␤1
CALCRL
D1, D5
D3, D4
ETA
ETB
EGF-R
GR
H2
Y1
trkB
LxR␣
OT
PAC1
EP2, EP4
IP
TGF-␤ II
TR
V1a
Rat, rabbit
Mouse
Human, rat, mouse, monkey
Rat, monkey, swine
Rat
Human
Mouse, rat
Human, rat, dog
Human
Rat
Rat
Mouse, rat
Mouse, rat
Rat
Mouse
Human
Human
Mouse
Mouse, human
Human
Mouse
Rat, mouse
Rat, mouse
Rat
Rat
Rabbit, mouse, rat, human
mRNA, functional (941, 943)
mRNA, functional (444)
mRNA, protein (258, 267, 316, 365, 437, 677, 718, 893, 991, 992)
mRNA, protein (42, 267, 365, 731)
Protein, functional (475, 622)
mRNA, functional (696, 820)
mRNA, protein, functional (553, 653)
mRNA, protein, functional (81, 161, 327, 513, 831, 935)
Protein (297)
mRNA, protein, functional (18, 19, 476, 636, 963)
mRNA, functional (745)
Protein, functional (737, 948)
Protein, functional (219, 463, 727, 948)
Protein (888)
Functional (444)
Functional (696)
mRNA (949)
Protein (257)
mRNA, protein, functional (599, 851)
Protein (35)
Functional (322)
mRNA, functional (241)
Functional (241, 401)
Protein (520)
Protein (545)
mRNA, protein (35, 36, 672)
CGRP, calcitonin gene-related peptide; ADM, adrenomedullin; ANP, atrial natriuretic peptide; EGF, epidermal growth factor; PACAP, pituitary
adenylate cyclase-activating polypeptide; PGE2, prostaglandin E2; TGF-␤, transforming growth factor-␤. Nomenclature is in accordance with
Alexander et al. (14). Reference numbers are given in parentheses.
Physiol Rev • VOL
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CASTROP ET AL.
with ANG II-AT1 receptor antagonists or reducing the
level of ANG II with ACE inhibitors causes a strong
increase in renin synthesis and release (127, 346). Likewise, the exogenous infusion of ANG II decreases renin
synthesis and renin release (775), suggesting that ANG II
may exert direct negative effects on this system. Further
support derives from mice lacking AT1a receptors, which
have an increased number of renin-positive JG cells (647).
Since changes in the systemic ANG II concentrations, as
well as alterations in the AT1 receptor density, modulate
the systemic blood pressure, an indirect effect of ANG II
on renin synthesis and secretion via the systemic blood
pressure cannot be excluded. However, it has also been
found that nonpressor doses of ANG II inhibit renin secretion, suggesting a blood pressure-independent inhibitory effect of ANG II on renin release (181, 293). Further
support for a pressure-independent effect of ANG II derives from the observation that ANG II inhibits renin
secretion from isolated perfused kidneys and from kidney
slices (616, 904). Such an inhibitory effect of ANG II on
renin is in accordance with the existence of AT1 receptors
on the JG cells (Table 3). ANG II has also been found to
decrease the COX-2 expression in MD cells via AT1 receptors at lower concentrations than needed for systemic
hemodynamic actions (984). Thus an inhibitory effect of
ANG II on renin synthesis and renin release via a suppression of COX-2-derived prostanoids from MD cells may
also be conceivable. Nevertheless, since JG cells are
equipped with ANG II AT1 receptors and because ANG II
has been shown to decrease renin synthesis and release in
As4.1 cells (105, 606), a direct negative effect of ANG II on
renin release and renin synthesis can be postulated. In
addition, it has been demonstrated that renal nerves are
not essential for the ANG II negative-feedback loop (924),
and this feedback loop is also relevant in various conditions of stimulated or reduced renin synthesis and secretion (802). However, a recent study in chimeric mice
carrying a regional null mutation of the AT1a receptor
questions the direct effect of ANG II on the JG cells. In
this report, the JGA of the AT1a receptor-deficient mice
were enlarged with intense expression of renin. In the
chimeric mice, the changes in the JGA were proportional
to the degree of chimerism, but the degree of JGA hypertrophy/hyperplasia and the expression of renin were unaltered in AT1a-expressing and AT1a-deficient JG cells
(568). More recently, renal cross-transplantation has been
combined with gene knockout technology. The AT1a receptor-deficient mice had increased renin mRNA and a
lower blood pressure than wild-type controls. Mice that
expressed the AT1a receptor only in the kidney or only in
extrarenal tissues had similar blood pressures; these were
lower than that of wild-type controls, but they were
higher than that of the complete AT1a-deficient mice. Renin mRNA levels in renal or extrarenal knockouts were
similar to wild-type controls but were significantly lower
Physiol Rev • VOL
than in complete AT1a-deficient mice (173). These data
therefore suggest that the renal AT1a receptors are key
determinants of blood pressure, but they may not be of
major importance for the regulation of renin expression.
Thus these two recent studies suggest that the regulation
of renin synthesis and release by ANG II is indirectly
mediated, likely via changes in systemic blood pressure.
In addition to the effect of circulating ANG II on the renal
renin synthesis and secretion, ANG II in the brain may
also have an inhibitory effect on the renin release. The
central administration of ANG II decreases renin secretion, and the central administration of losartan increases
renin secretion (387, 573, 942, 968). This effect on renal
renin secretion is likely due to a reduction in the renal
sympathetic nerve activity (574). Moreover, it should be
kept in mind that ANG II facilitates the release of norepinephrine from the renal sympathetic nerve terminals
(193).
In summary, ANG II inhibits renin release and synthesis through a direct short negative-feedback loop and
also via indirect mechanisms.
3. ANP
The 28-amino acid peptide ANP is mainly released by
the cardiac myocytes of the atrium in response to atrial
stretch. The cardiovascular and renal effects of ANP (hypotension, natriuresis, and diuresis) counteract the effects of ANG II (837). ANP can modulate the renin release
through direct and indirect mechanisms. The activation of
the natriuretic peptide receptor-1 (NPR1) can directly
inhibit the renin release by increasing the cGMP formation. Although it is generally believed that the tubular
action of ANP is predominantly exerted in the more distal
segments of the nephron, ANP may also indirectly reduce
the renin release via a possible effect on the proximal
tubular salt reabsorption (314), which may lead to an
increased NaCl load at the MD. In contrast, ANP can
indirectly stimulate renin release by lowering the blood
pressure. Indeed, somewhat conflicting data have been
reported regarding the role of ANP in renin release, although most of these studies, including in vitro studies
using isolated JG cells, suggest that ANP is an inhibitor of
renin release (293). More recent studies found that the
incubation of rat renal cortical slices with or intravenous
infusion of ANP into humans did not affect the renin
release (377), whereas the intrarenal and intravenous infusion of ANP in dogs stimulated and inhibited renin
release, respectively (213). ANP-deficient mice have
lower renal renin mRNA levels but increased plasma renin
concentrations and are hypertensive (576, 638). In addition, the genetic deletion of the NPR1 receptor leads to
hypertension, which is paralleled by a reduction in the
plasma renin concentration and in renal renin expression
(797). The increase in systemic blood pressure observed
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in the ANP- and NPR1-knockout mice may indirectly mediate the inhibition of the renal renin gene expression.
Taken together, an inhibitory effect of ANP on the
renin secretion at the JG cell level has been demonstrated
(411, 475). The inhibition of renin release by ANP may be
modulated by the cardiovascular and renal effects of ANP
in vivo.
4. Vasopressin
Arginine vasopressin (AVP), also known as antidiuretic hormone (ADH), influences a wide variety of physiological functions; more specifically, the induction of
antidiuresis and vasoconstriction are considered the most
important effects of AVP. AVP acts on three G proteincoupled receptors, termed the vasopressin V1a, V1b, and V2
receptors (44, 891). In the kidney, the V1a receptors,
which mediate the vasoconstrictor effect of AVP, are
localized in the renal vasculature, the JG apparatus, the
MD cells, the connecting tubule, and the cortical collecting duct (28, 35, 672). The V2 receptor expression, which
mediates the antidiuretic effect of AVP, has been found in
the TAL, the MD cells, the distal convoluted tubule, the
connecting tubule, and the collecting duct (614, 672). The
renal expression of the V1b receptor has also been reported, but the precise localization and function of this
receptor are unclear (531, 595).
AVP also modulates renin release, and the inhibitory
effect of AVP on renin release was favored by older
investigations (293). Among other findings, AVP has been
shown to decrease renin release from primary cultures of
renin-producing JG cells (485). Because vasopressin V1a
but not V2 receptor expression has been described for the
afferent arteriole (35, 614, 672), one may assume that this
inhibitory effect could be mediated via vasopressin V1a
receptors (776). In line with this assumption, it has been
found that the preferential V1a agonist terlipressin decreased the plasma renin concentration in patients with
hepatorenal syndrome (294, 897). However, terlipressin
also improved the renal function and blood pressure (605,
897). Contrary to these findings, it was recently reported
that PRA and renin mRNA were lower in the vasopressin
V1a receptor-deficient mice compared with wild types
(28). The decrease in the renin system in these mice was
paralleled by a decreased expression of nNOS and COX-2
in MD cells and alterations in systemic and renal hemodynamics, such as lower blood volume, hypotension, decreased renal blood flow, and GFR (28, 459). Since the
expression of vasopressin V1a receptors has been found in
MD cells (28), AVP may also influence renin release via a
MD-dependent mechanism. AVP may also modulate the
renin system via the vasopressin V2 receptors. It has been
found that the infusion of the vasopressin V2 receptor
agonist desmopressin (dDAVP) decreases blood pressure
and increases the PRA in humans (47, 72). Subsequently,
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it was reported that the stimulatory effect on renin release
was inhibited by the COX inhibitor indomethacin, independent of the blood pressure-lowering effect of dDAVP
(319). However, the infusion of dDAVP into humans and
animals also increases the renal blood flow and GFR,
probably due to a vasodilatation of the afferent arteriole
(86, 231, 619, 701, 849). A stimulatory effect of dDAVP on
renin release has been reported for the isolated perfused
rat kidney and from rabbit renal cortical slices (319, 762),
and chronic infusion of dDAVP has been shown to increase renin mRNA levels in Brattleboro rats, which lack
AVP (20). Although these data support a stimulatory role
for the vasopressin V2 receptor in renin release, it has
recently been found that renin mRNA is also increased in
vasopressin V2 receptor-deficient mice (759), which exhibit a clear renal phenotype (981). Furthermore, the
vasopressin V2 receptor antagonist tolvaptan did not
change the plasma renin activity in rats and humans (800,
801, 911).
Due to its complex cardiovascular and renal effects
in vivo, the role of vasopressin and the respective receptors in the control of renin release is still controversial
and needs further evaluation. One could assume that AVP
inhibits renin release under some conditions via the activation of the vasopressin V1a receptors, but it may also
increase renin secretion via the activation of V2 receptors.
5. Oxytocin
In addition to its well-known effects on uterine contraction and milk ejection, oxytocin has been shown to
influence renal function, such that oxytocin increases the
GFR and natriuresis in rats (167). Oxytocin activates a
single G protein-coupled receptor, termed the OT receptor (268). Because the expression of OT receptors has
been found in MD cells (35, 658, 828), a role for oxytocin
in renin release was presumed. It has been reported that
oxytocin increases the plasma renin concentration in rats
and that this increase may be independent of the oxytocin-induced natriuresis (810). Subsequently, it was found
that oxytocin-induced renin secretion was inhibited by
␤-adrenergic receptor antagonism (360), but not by
renal denervation (530). Therefore, circulatory catecholamines may be involved in renin release in response to oxytocin. Because oxytocin is released in
response to hypotension and hypovolemia, it has been
speculated that oxytocin could stimulate renin release
under these conditions. The OT receptor antagonist atosiban attenuates the rise in PRA and heart rate in response
to hydralazine or diazoxide, without affecting the blood
pressure-lowering effect of these two vasodilatators
(361). In contrast to these findings, the intravenous infusion of oxytocin decreased urine flow and reduced sodium excretion and PRA in humans (716). The opposite
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finding in humans may be due to a different expression of
the renal OT receptors (35).
In summary, oxytocin stimulates renin secretion in
laboratory animals via a ␤-adrenergic-dependent mechanism. The stimulatory effect may be species dependent,
probably due to a different expression of renal OT receptors.
6. Aldosterone
The stimulation of renin release increases the plasma
levels of ANG II, which subsequently stimulates the secretion of aldosterone from the adrenal glands (821). The
stimulation of angiotensin II and aldosterone formation
increases the sodium reabsorption and consequently increases the body sodium content, which, in turn, inhibits
the renin gene expression (293, 488, 821). Recently, it was
shown that JG and As4.1 cells express mineralocorticoid
receptors; additionally, aldosterone increased renin
mRNA levels in primary cultures of mouse JG cells prestimulated with isoproterenol, but it had no effect on the
exocytosis of stored renin (444). Conversely, mineralocorticoid receptor- and aldosterone synthase-deficient
mice have a strong increase in plasma renin concentration, probably due to a sodium deficit caused by renal
sodium wasting (71, 555).
These data, therefore, suggest that aldosterone exerts a direct positive effect on renin gene expression at
the cellular level, probably by stabilizing renin mRNA.
However, the in vivo relevance of this finding remains
unclear, and therefore, further investigation is necessary.
Moreover, the in vivo effect of aldosterone may be indirectly due to changes in the body sodium content, extracellular volume, or blood pressure.
7. Glucocorticoids
It is well known that the administration of glucocorticoids increases the GFR via a vasodilatation of afferent
and efferent arterioles and increases the renal blood flow
and blood pressure (56, 82, 183, 950). Several findings
suggest that glucocorticoids also regulate renin synthesis
and renin release. In sheep, a birth peak of cortisol seems
to be responsible for the parallel activation of renin
(231a). Furthermore, glucocorticoids have been found to
directly activate renin synthesis in JG cells (444). Glucocorticoids act on glucocorticoid receptors (GR), which
have been mainly localized in the glomeruli, proximal
tubule, and TAL segments, including the MD cells (549,
879a). In addition, cortisol can bind and activate the mineralocorticoid receptor (MR). However, the 11␤-hydroxysteroid dehydrogenase type 2 enzyme (11␤-HSD2) is
mostly coexpressed with the MR and inactivates cortisol
to cortisone, which is not able to bind to the MR. Since
afferent arterioles, isolated JG cells, and As4.1 cells express 11␤-HSD2, a direct mineralocorticoid effect of the
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glucocorticoids on renin release and synthesis may be
unlikely (444, 895a). In addition, the glucocorticoids may
indirectly induce renin release via a possible effect on the
proximal tubular salt reabsorption, which may lead to a
decreased NaCl load at the MD (634).
On the other hand, it has been found that cortisol can
reduce the plasma renin activity in adult ewes (425). The
treatment of rats with dexamethasone did not alter the
PRA, although it did strongly increase the blood pressure
(838). Furthermore, COX-2 expression in the TAL and in
the MD cells is suppressed by endogenous glucocorticoids (549, 915, 984).
Taken together, a direct stimulatory effect of glucocorticoids on renin synthesis has been shown in vitro.
The stimulatory effect of glucocorticoids on renin release
and synthesis may be modulated by an increase in blood
pressure and by the suppression of the MD COX-2-derived
prostanoids in vivo.
8. Thyroid hormone
Several in vivo and in vitro studies have suggested
that the thyroid hormone influences renin synthesis and
secretion. Hyperthyroidism in response to L-thyroxine or
triiodothyronine (T3) treatment increased, while hypothyroidism due to thyroidectomy or methimazole treatment
reduced, the PRA and renin mRNA in rats and fetal sheep
(144, 145, 207, 446, 560). Moreover, the stimulation of
renin synthesis and renin secretion by thyroid hormone
seems to be independent of sympathetic nerve activity,
since the chemical sympathetic denervation with 6-hydroxydopamine did not affect the stimulatory effect of the
thyroid hormone on renin synthesis and renin secretion
(447). In vitro, thyroid hormone enhanced renin secretion
from rat kidney slices and from primary cultures of JG
cells (320, 367). In addition, renin mRNA was found to be
increased in primary cultures of JG cells by T3 and in rats
in response to L-thyroxine (367, 446). These observations
suggest a possible direct effect of thyroid hormone on the
activity of the renin system. Subsequently, it was found
that thyroid hormone induces the promoter activity of the
human renin gene through thyroid hormone response
element-dependent mechanisms in Calu-6 cells (445).
9. Sex steroids: testosterone, estrogen, and
progesterone
Various studies have indicated that blood pressure is
higher in men than in women and that blood pressure
increases after menopause in women (107, 430, 565, 823).
In addition, the increase in blood pressure starts with
puberty, suggesting a role of the sex steroids (39, 317).
Sex-dependent differences in blood pressure are also
known for several animal models (289, 351, 431, 719).
Male spontaneously hypertensive rats (SHRs), for example, have higher blood pressure than females, and orchi-
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dectomy, but not ovariectomy, attenuated the increase in
systolic blood pressure (148, 217). Since the renin-angiotensin system is a major system for the long-term control
of blood pressure and salt and water homeostasis, genderdependent differences in the synthesis and release of
renin from the kidney may be involved in the sex-dependent blood pressure regulation. It has been found that the
PRA is higher in men than in women and that it increases
in postmenopausal women (395, 774). The chronic treatment of gonadectomized SHRs with testosterone increases blood pressure and PRA in male and female
SHRs, and PRA decreases with castration in male rats
(149, 217). Furthermore, the administration of testosterone increases the PRA and blood pressure in normotensive rats (719), and application of the testosterone receptor antagonists cyproterone acetate or flutamide attenuated
the development of hypertension in male stroke-prone SHRs
and reduced the renin synthesis and secretion in female
TGR(mREN2)27 rats and mice (45, 256). Thus it has been
suggested that androgens may have a stimulatory effect
on renin secretion. Androgens, such as testosterone and
dihydrotestosterone (DHT), act on androgen receptors,
which are expressed in mammalian kidneys (739). Although the precise localization of these receptors is not
entirely clear, it seems likely that the androgen receptors
are mainly expressed in proximal tubular cells where
testosterone enhances the salt and water reabsorption,
likely via an increased expression of the proximal tubular
transporter NHE3 (705, 739). There is no evidence for the
expression of testosterone receptors in JG cells or MD
cells. In line with this, testosterone did not alter the levels
of renin mRNA in the As4.1 cell line (444). Otherwise, no
effect, or a decrease in renal renin mRNA expression, has
also been reported for mice (132, 700, 928). As a result,
testosterone may indirectly influence the renin system,
likely via an increased absorption of salt and water at
the proximal tubule, which may lead to a decreased
NaCl load at the MD. This effect may be modulated by
an increased extracellular volume and increased blood
pressure in vivo.
In contrast to androgens, estrogens tend to have
antihypertensive effects, mainly via the control of local
blood flow and peripheral resistance due to alterations in
the release of the endothelial mediators (359, 551). Interactions between estrogens and renin have also been reported. Several studies support a stimulatory effect of
estrogen on renin release. Increases in endogenous estrogen levels are associated with increased PRA. In healthy
women, for example, the PRA increases during the luteal
phase of the menstrual cycle, when plasma estrogen levels are highest (137, 153, 787). Furthermore, estrogen
administration in animals increased the PRA, which was
paralleled by a decrease in blood pressure (550, 551), and
estrogen replacement increased the PRA in cynomolgus
monkeys (89). On the other hand, it has also been found
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that, after menopause, blood pressure and PRA increase
in women, and the renin levels in women with estrogen
replacement therapy were lower than in those without
estrogen therapy (178, 774). In animals, estrogen administration reduced the PRA and blood pressure in ovariectomized mRen(2) Lewis rats (138). The mechanism for a
possible modulatory effect of estrogen on the renin secretion is not understood. Moreover, the information on the
renal distribution of the estrogen receptor is rather limited (739), and no expression has been reported for the
MD cells (698, 829). Whether the JG cells contain estrogen
receptors has yet to be determined. Since estradiol did
not alter the renin mRNA in the As4.1 cell line (444), it
seems likely that indirect, rather than direct, mechanisms
may be involved in the modulation of renin secretion by
estrogens. In this regard, estrogen has been reported, for
example, 1) to increase the renal oxytocin receptor gene
expression (659), 2) to attenuate the response of ANG II
on the AT1 receptors (34, 252, 628, 804), 3) to increase the
renal NO synthesis (55), 4) to modulate the bradykinin
B2-receptor gene expression and function (547), and 5) to
inhibit the sympathetic nervous system (187, 234, 523). In
addition, during low estrogen levels, the effect of androgens on renin release may be more apparent (719). Taken
together, the influence of estrogen on the renal release of
renin remains controversial mainly due to the complex
influences on the cardiovascular functions in vivo.
Progesterone acts on progesterone receptors, but the
precise renal localization of these receptors is not clear
(739). With regard to renin synthesis and renin release, it
has been reported that the administration of progesterone
increases PRA in humans (642). Furthermore, the increase in PRA during the menstrual cycle was attenuated
by a synthetic progesterone (641). In addition to an action
on the progesterone receptors, progesterone can also act
as a mineralocorticoid receptor antagonist (98). Thus the
natriuretic and blood pressure-lowering actions of progesterone have mainly been related to this antagonistic
effect (136, 642, 707). Therefore, progesterone may also
attenuate the action of aldosterone on renin synthesis and
renin release. In addition, progesterone can be metabolized to testosterone and dihydrotestosterone in the kidney and may therefore have androgenic effects, probably
also on renin release (706).
10. Adipokines: leptin and adiponectin
Obesity is a major risk factor for the development of
hypertension (232, 301). The activation of the sympathetic
nervous system and of the RAAS, as well as the endothelial and renal dysfunctions, has been implicated in the
association between obesity and hypertension (710). In
the past few years, it has become apparent that adipose
tissue is not only a reservoir for energy, but it is also an
endocrine organ, which secretes a variety of bioactive
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peptides, known as adipokines (427). Among these, leptin
and adiponectin in particular have been suggested to be
involved in the development of obesity-induced hypertension and, therefore, also for the activation of the RAAS in
obesity.
Leptin, the product of the obesity gene, is a circulating peptide that is primarily synthesized and secreted by
the adipocytes. Originally, it was described as an adipostat that controls energy balance (532, 585). Later on, it
was observed that leptin also influences the cardiovascular and renal functions and that the increased levels of
leptin in obesity may contribute to obesity-induced hypertension. It has been found, for example, that the infusion
of leptin activates sympathetic nerve activity and increases the mean arterial blood pressure, heart rate, urine
volume, and sodium excretion in rats (323, 389, 793, 914).
Reports of a positive correlation between leptin and PRA
in obesity and essential hypertension in humans suggest a
potential role for leptin in renin release (5, 836, 894), but
up to now, no direct effect of leptin on the release of renin
from the kidney has been reported. In contrast, the carotid artery or intravenous infusion of leptin did not alter
PRA in rats (793, 914). However, leptin may indirectly
induce renin release via a central activation of the renal
sympathetic nervous system (120, 323, 561, 711, 712, 910).
In accordance with this, it has been reported that renal
denervation inhibits the rise in PRA, at least in response
to a high-fat diet in dogs (421).
Adipocytes also secrete adiponectin, a peptide that
has been described to enhance insulin sensitivity and
prevent arteriosclerosis (644, 964). The plasma levels of
adiponectin have been found to be lower during obesity
and in hypertensive men, and they are negatively correlated with blood pressure (33, 385, 509). Adiponectin has
been found to ameliorate obesity-related hypertension in
mice (643) and to decrease blood pressure and renal
sympathetic nerve activity in rats (856). Furthermore, the
inhibition of the RAAS increases and infusion of ANG II
decreases plasma adiponectin levels (249, 509). It is unknown whether there is a direct effect of adiponectin on
renal renin release. However, since adiponectin decreases
the renal sympathetic nerve activity, it may indirectly
influence renal renin release.
11. Growth hormone and insulin-like growth factor I
The administration of growth hormone (GH) into
healthy men increases the PRA without changes in blood
pressure or decreases in the sodium and water excretion
(340, 590). In line with these findings, the inhibition of the
RAAS prevented the GH-induced fluid retention in humans (592). Furthermore, GH was found to increase the
PRA in GH-deficient humans and rats (175, 347, 588, 589,
959). Consistent with a stimulatory effect of GH on renin
release, it has been found that a growth hormone receptor
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deficiency results in reduced plasma renin concentration
despite a decrease in blood pressure (212). The stimulatory effect of GH on renin release may be due to an
increased formation of COX-derived prostanoids (310).
It has been suggested that several effects of GH are at
least partly mediated by insulin-like growth factor I
(IGF-I) (591). Indeed, it has been found that IGF-I increases PRA in rats and fetal sheep and stimulates the
secretion of renin from renal cortical slices (392, 408, 563,
564), but the precise role of IGF-I for GH-induced renin
release is unknown. On the other hand, no effect of GH on
the PRA and renin mRNA or on the secretion of renin
from primary cultures of JG cells have been reported (51,
333, 413, 468).
In summary, it can be concluded that GH stimulates
renin synthesis. Since GH did not induce renin release
from the JG cells, the effect of GH on renin secretion may
be rather indirect and may depend on the formation of
COX-derived prostanoids.
12. Prostanoids
PGI2 and PGE2 are direct stimulators of renin synthesis and secretion that most likely function via enhanced cAMP formation (293). Due to their short half-life
time, it is still unclear whether extrarenal-derived PGI2
and PGE2 could serve as stimulators of renin secretion
and synthesis. Therefore, PGI2 and PGE2 have been suggested to function as local, rather than systemic, regulators of these processes (see sect. IV, A1 and B4). However,
since PGI2 is not completely metabolized when it passes
through the pulmonary system and since the half-life of
PGI2 is between 30 s and several minutes (541, 594, 906),
it may be theoretically possible that systemic-derived
PGI2 is of relevance for renal renin release under certain
circumstances, such as furosemide treatment or sepsis
(93, 345, 518).
13. Dopamine
The neurotransmitter dopamine modulates several
physiological functions within the kidney, including renin
release and sodium excretion. Dopamine can directly
stimulate renin release via the activation of the D1-like
receptors upon the dopaminergic innervation of the vascular pole of the glomerulus. Increases in the systemic
dopamine concentration can also indirectly affect renin
release by lowering blood pressure. In addition, dopamine
can negatively influence renin release and synthesis via its
effect on the proximal tubular sodium reabsorption. This
effect is important because the main source of dopamine
within the kidney is the proximal tubule itself. Here, the
glomerular filtered dopamine precursor L-DOPA is reabsorbed and then converted into dopamine by the action of
aromatic L-amino acid decarboxylase, which is strongly
expressed in proximal tubular cells. Therefore, dopamine
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signaling leads to an increase in the tubular sodium chloride concentration at the MD (293).
Most investigators have observed a stimulatory effect
of dopamine on the renin secretion at the level of kidney
slices, isolated perfused kidneys, and in vivo (293). Two
recent studies further support a stimulatory role for dopamine in renin synthesis and secretion. The authors
reported that dopamine induces renin release from rat JG
cells (963) and isolated glomeruli via DA1 receptors (307).
The effect of dopamine on renin release was also recently
investigated in mice carrying a genetic deletion of catechol-O-methyltransferase (COMT), the main enzyme in
the renal metabolization of dopamine. These data suggest
that dopamine inhibits renin release and synthesis indirectly via increased NaCl load at the MD during normovolemia or hypovolemia; moreover, the data suggest that
dopamine directly stimulates renin release in situations of
volume expansion (985).
In summary, dopamine can directly stimulate renin
release and synthesis, most likely via DA1 receptors at the
JG cell level. However, the direct stimulatory effect of
dopamine on renin release and synthesis is largely compensated for by the indirect inhibitory cardiovascular and
renal effects of dopamine in vivo.
14. Succinate/GPR91
The orphan G protein-coupled receptor GPR91 has
recently been shown to function as a receptor for succinic
acid. GPR91 mRNA was found to be expressed predominantly in the kidney and, at lower levels, in the liver and
spleen. The in situ hybridization revealed GPR91 expression in the proximal tubules, distal tubules, and the JGA
of the mouse kidney. The intravenous injection of succinate increased PRA in Sprague-Dawley rats (324), confirming a report that examined the rate of renin release
from viable JG cells during the superfusion of isolated rat
glomeruli (53). Moreover, blood pressure also increased
in response to succinate in a dose-dependent manner. The
increase in blood pressure was eliminated in the bilateral
nephrectomized animals, attenuated in the animals pretreated with the ACE inhibitor captopril, and absent in the
GPR91 knockout mice. Because these authors found that
GPR91 is a Gq- and Gi-coupled receptor, it seems unlikely
that GPR91 directly influences renin secretion (324). Recently, it was demonstrated that MD cells express the
GPR91 protein in the apical membrane and that the treatment of MD cells with succinate activates the mitogenactived protein kinase (MAPK) pathway, leading to an
increase in the COX-2 derived PGE2. In line with these
in vitro findings, succinate-induced renin release from
microperfused JGA was eliminated by the inhibition of
MAPK and COX-2 (908).
Increased plasma succinate levels were found in several animal models of hypertension, including SHR, and
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diabetes, but they were not found in human hypertensive
or diabetic patients (740). Animal studies suggest that the
GPR91 receptor may be of relevance for the stimulation of
renin release in response to high glucose levels (887), in
experimental diabetes (908), and likely in response to low
sodium intake (908).
In summary, it can be concluded that the succinate/
GPR91 system enhances renin synthesis by a direct effect
of succinate on GPR91 expressed in the JGA/glomerulus.
15. PACAP
PACAP is involved in the regulation of the cardiovascular and central nervous system (909). PACAP was recently shown to dose-dependently stimulate renin secretion from isolated perfused kidneys of rats and from
primary cultures of renin-producing JG cells. The PACAPinduced renin release from isolated kidneys was attenuated in pituitary adenylate cyclase 1 (PAC1) receptordeficient mice, which also exhibited lower basal PRC and
lower blood pressure. Moreover, the PRC was lower in
PAC1 receptor knockout mice fed a low- or high-salt diet,
compared with the wild-type mice, and in response to
treatment with the ACE inhibitor ramipril, although the
principal regulation was not attenuated. Therefore, it may
be inferred that PACAP is a tonic enhancer of the renin
system in vivo via the activation of adenylyl cyclases
(322).
16. Bradykinin
The renal and cardiovascular activities of bradykinin,
the enzymatic product of the kallikrein-kinin system, are
primarily mediated via the activation of the bradykinin B2
receptor, which is constitutively expressed in the vascular
endothelium and mediates the vasodilator effects of kinins (274, 721). Although some studies found a stimulatory effect of kinins on renin release, other investigators
have observed no effect (293). Accordingly, studies using
the B2 receptor-deficient mice have also produced conflicting results. The B2 receptor knockout mice on a
129SvxC57Bl/6J background were hypertensive compared with the wild-type mice on a 129Sv/J background.
However, the PRA and renin expression did not differ
between the strains (548). The B2 receptor-deficient mice
that were backcrossed onto a C57BL/6 background were
normotensive, had a lower heart rate, exhibited decreased renal blood flow, and possessed higher renal
renin mRNA expression compared with wild-type controls (889). Mice lacking tissue kallikrein, which is the
main kinin-forming enzyme in vivo, exhibited normal
blood pressure and normal renal blood flow, but they
displayed decreased renal renin mRNA expression (889).
Another study examining the B2 receptor-deficient mice
on a C57BL/6 background reported lower renal renin
protein levels and decreased renin mRNA abundance.
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Renal tissue levels of angiotensin I were found to be
diminished in these B2 receptor knockout mice, while the
ANG II levels were reportedly unchanged. In addition,
these authors observed decreased renal COX-2 gene expression in the B2 receptor knockout mice (374). They
concluded that the B2 receptor-dependent regulation of
COX-2 participates in the basal control of renin gene
expression. With regard to the lower renin mRNA expression, a similar finding was reported for the newborn and
adult B2 receptor-deficient mice (976). In addition, kidney
renin mRNA levels did not differ between the B2 receptordeficient mice and wild-type controls during normal and
chronic high salt intake (134). The role of the bradykinin
B2 receptor was further investigated in mice overexpressing the human version of the protein. These hypotensive
mice exhibited enhanced renal function with increased
urinary excretion of nitrite/nitrate cGMP, cAMP, and kinin. However, the renal renin mRNA abundance was not
altered in these mice (933).
The treatment of rats with HOE-140 (Icatibant), a
B2 receptor antagonist, or the kallikrein inhibitor aprotinin did not alter basal renal renin mRNA abundance
(215, 977). The intravenous infusion of HOE-140 decreased the basal PRA in rabbits independent of any
changes in blood pressure, but it did not attenuate the
furosemide-stimulated elevation in the PRA (155).
HOE-140 did not alter the basal PRA or the furosemideor valsartan-induced PRA changes in humans (504,
612). However, HOE-140 inhibited the increase in PRA
and the decline in blood pressure observed in response
to captopril in humans (251). In contrast, HOE-140 did
not alter the basal or enalapril-induced PRA and PRC
changes in rats with passive Heymann nephritis, although HOE-140 attenuated the decreased blood pressure effect of enalapril (363). Moreover, the DOCAsuppressed PRA was not altered by HOE-140 in rats
(546).
In summary, the precise role of bradykinin in renin
synthesis and secretion is still controversial, probably
because of the complex nature of the cardiovascular and
renal effects of bradykinin in vivo.
17. Adrenomedullin
Adrenomedullin (ADM) is a peptide with renal and
cardiovascular activities, and the immunoreactivity of
the proadrenomedullin NH2-terminal 20-amino acid
peptide has been localized in the JG cells (536). The
plasma levels of ADM have been shown to significantly
correlate with the PRA in patients with heart failure
(422) and cirrhosis (450), suggesting a potential role for
ADM in the secretion of renin. Accordingly, the intravenous administration of ADM in rabbits and sheep
caused a decrease in the mean arterial blood pressure,
which was paralleled by increases in the heart rate and
Physiol Rev • VOL
PRA (141, 247, 673). In addition, ADM infusion into
healthy volunteers or patients with heart failure, essential hypertension, or chronic renal impairment increased the PRA (495, 496, 572, 892). This effect was
not observed in patients with pulmonary hypertension
(618). Subsequent studies demonstrated that the renin
release from isolated perfused rat kidneys is dosedependently increased by ADM (397) and that ADM
stimulates renin release and renin mRNA synthesis in
mouse JG cells, suggesting a direct effect in renin
synthesis (397). On the other hand, it has been reported
that the intrarenal infusion of ADM in dogs increased
the renal blood flow, urine flow, and urinary excretion
of sodium and potassium without alterations in blood
pressure, heart rate, or PRA (209, 409). Similarly, ADM
infusion attenuated the rise in PRA and blood pressure
due to left renal artery clipping in rats (428). In addition, a negative correlation was found between the
plasma ADM concentrations and PRA in patients with
chronic glomerulonephritis (438). Recently, it was reported that the infusion of ADM-2, a new member of the
calcitonin gene-related peptide superfamily, increased
the PRA in normal conscious sheep (140). Taken together, a direct stimulatory effect of ADM on renin
secretion at the JG cell level has been shown, although
this effect may be modulated by the cardiovascular and
renal effects of ADM under certain in vivo circumstances. The possible stimulatory effect of ADM-2 warrants further investigation.
18. Neuropeptide Y
The vasoactive peptide neuropeptide Y (NPY) is
coreleased with norepinephrine from sympathetic nerve
terminals. In addition to the expression of the NPY receptor subtype Y1 in the collecting ducts and the loop of
Henle, the Y1 receptor expression has been described for
the JGA (949). Therefore, a possible role for NPY in the
release of renin has been suggested. It has been shown
that the infusion of NPY inhibited renin secretion in isolated perfused rat kidney and in animal models, which
was paralleled by renal vasoconstriction (77, 168, 292).
Furthermore, NPY was found to decrease the PRA in
adrenalectomized rats (693), in postmyocardial infarction
rats (982), in response to isoproterenol or epinephrine
(10, 38, 221), and in two-kidney one-clip renal hypertensive rats (920). On the other hand, no changes in PRA in
response to nonpressor doses of NPY have also been
reported (37, 221, 684, 920, 982). In addition, no effect of
NPY was observed on renin release from renal cortical
slices (798). Furthermore, no renal phenotype has been
reported in mouse models deficient in NPY or in Y1 receptors (953), although the administration of NPY has
been found to decrease the renal blood flow and to induce
diuresis and natriuresis (78).
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Taken together, NPY may inhibit renin release under
some experimental conditions or with pharmacological
doses, but it does not seem to be involved in the physiological control of renin secretion.
V. ACTION OF RENIN
Most of the major known effects of the reninangiotensin system (RAS) are related to the activity of
angiotensin II (ANG II). Consequently, the end point of
the renin-angiotensin cascade is generally assumed to
be the generation of ANG II and related peptides. In this
section, we briefly overview the data relevant to the
signaling and function of the various angiotensin receptors, as reviewed in more detail elsewhere (575). In
addition, we discuss data showing how angiotensin
receptors are subject to regulatory processes, including
changes in the angiotensin receptor expression, receptor desensitization/internalization, and dynamic interaction with angiotensin receptor-binding proteins. Furthermore, there is growing evidence that alternate peptides like ANG-(1–7) and their respective receptors
broaden the functional range of the RAS. Finally, the
action of renin is not restricted to its proteolytic activity and subsequent angiotensin generation; there is accumulating evidence that renin and/or pro-renin exert
direct effects upon binding to renin/pro-renin receptors
(Fig. 6).
A. AT1 and AT2 Receptors
Two receptor subtypes for ANG II have been characterized, AT1 and AT2. In rodents, AT1 exists as two highly
homologous subtypes, AT1a and AT1b. While AT1a and
AT1b have similar functions under most conditions, AT2mediated signaling differs considerably from AT1-dependent signaling, as it partly antagonizes the effects of ANG
II on AT1 receptors.
1. AT1, AT1a, and AT1b receptor function and
signaling
AT1 receptors mediate most of the known effects
of ANG II. The AT1 receptor, a 40-kDa protein consisting of 359 amino acids, is a member of the seventransmembrane domain G protein-coupled receptor
family. The AT1 receptors typically couple to Gq complexes, resulting in the activation of downstream intracellular signaling pathways that lead to the activation
of phospholipase C, phospholipase A2, and phospholipase D (898). The activation of phospholipase C triggers the enhanced formation of IP3 and diacylglycerol,
promoting the subsequent release of calcium from intracellular stores and the activation of PKC, respecPhysiol Rev • VOL
FIG. 6. Multiple effector systems of the renin-angiotensin system.
ANG 0, angiotensinogen; ANG I, angiotensin I; ANG II, angiotensin II;
ACE, angiotensin I converting enzyme; ACE-2, angiotensin converting
enzyme type 2; ANG 1–9, angiotensin nonapeptide; ANG 1–7, angiotensin
heptapeptide; Mas-R, Mas receptor.
tively. For a comprehensive review of the manifold
intracellular signaling processes triggered upon the
binding of ANG II to AT1 receptors, see Reference 575.
In most mammalian species, there is only one distinct
type of AT1 receptor. However, in rats and mice, two
isoforms of AT1 exist, AT1a and AT1b. They share high
amino acid homology (⬎95%), and so far, no pharmacological tools have been available to specifically, or
even preferentially, block one of the isoforms (280).
ANG II exerts myriad functions via AT1, including but
not limited to vasoconstriction, increased renal tubular
salt reabsorption, stimulation of aldosterone release, and
central effects like elicitation of thirst and vasopressin
secretion. Under pathological conditions, ANG II was
shown to promote vascular remodeling, cardiac hypertrophic remodeling, and extracellular matrix deposition
(206).
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In view of these multiple functions and considering
the broad expression pattern of AT1 receptors in almost
all organs, it is not surprising that mechanisms have
evolved to regulate AT1 receptor function, both spatially
and temporally. These mechanisms include 1) regulation
of AT1 receptor transcription, 2) regulation of AT1 receptor surface expression via internalization and membrane
recycling, and 3) modulation of AT1 receptor activity by
accessory proteins.
2. Regulation of AT1 receptor transcription
The chronic elevation of ANG II levels in vitro has
been reported to activate a feedback loop that results in
the downregulation of the AT1 receptor expression (279,
284, 501). Unfortunately, the situation in vivo is less clear.
During a low-salt diet, and by inference elevated ANG II
levels, the downregulation of the AT1 receptor expression
in the rat liver has been reported (150, 760). The regulation of AT1 expression in the kidney under a low-salt diet
is spatially heterogeneous. AT1 expression was also found
to be upregulated in the proximal tubule but downregulated in glomeruli (150). In the adrenal gland, AT1 expression was augmented during a low-salt diet (384, 506, 760).
These diverse results clearly suggest that multiple factors
affect AT1 receptor expression in response to a salt-restricted diet. In fact, AT1 expression was shown to be
regulated by numerous factors other than ANG II. These
include low-density lipoprotein (629), insulin (845), and
progesterone (630); meanwhile, ANG II (284), NO (371),
and estrogens (630) suppress AT1 expression. Thus modulation of AT1 expression may constitute a measure to
locally adapt the sensitivity of target cells and organs
when they are exposed to changes in systemic ANG II
levels. For example, a salt-restricted diet, accompanied by
enhanced systemic ANG II concentrations, stimulates various salt-conserving mechanisms, like aldosterone release
and renal sodium reabsorption, but it has little, if any,
effect on the vascular resistance. It remains to be determined to what extent the modulations of AT1 receptor
expression are relevant for this apparent local fine-tuning
of ANG II sensitivity.
3. Regulation of AT1 receptor surface expression by
internalization and membrane recycling
AT1 receptors are subject to internalization and
desensitization. The continuous cycle of receptor internalization and cell surface retrafficking was shown to
be shifted towards internalization upon binding of ANG
II to the AT1 receptor. As a consequence, the number of
available receptors in the cell membrane was reduced,
resulting in cell desensitization for ANG II (205, 279,
284). In addition, AT1 receptors located in the cell
membrane are also subject to direct desensitization.
Various members of the G protein-coupled receptor
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kinase family (GRK; Refs. 505, 529), including GRK2,
GRK3, and GRK5, were found to be capable of phosphorylating serine and threonine residues located in the
cytoplasmic domain of AT1 receptors. The phosphorylation of AT1 resulted in inactivation of the cell membrane-bound AT1 and promoted receptor internalization (412, 649).
In summary, the AT1 receptor internalization and
surface trafficking permit regulation of the AT1 receptor
surface expression and, consequently, influence the magnitude of local ANG II effects.
4. Modulation of AT1 receptor activity by accessory
proteins
The set of molecular mechanisms that modulates AT1
receptor signaling also includes the interaction of AT1
with AT1-associated proteins. During the last few years,
four different proteins that interact with the COOH-terminal, intracellular tail of the AT1 protein have been identified. These AT1-associated proteins include negative and
positive regulators of AT1 signaling. The AT1-associated
protein Atrap (angiotensin receptor-associated protein)
was identified as a negative regulator of AT1 (180),
whereas ARAP1 (angiotensin receptor-associated protein
1 ⫽ angiopoietin-related protein 2; Ref. 286) and GLP
(GEF-like protein) exert positive regulatory functions.
ARAP1 overexpression in the proximal tubule of mice
results in hypertension and kidney hypertrophy, suggesting that ARAP1 may function as a positive regulator of the
AT1 receptors (285). The function of the fourth known
AT1-associated protein, EP24.15 (metalloendopeptidase
24.15), remains unknown (799).
5. Atrap: a negative regulator of AT1 receptors?
The investigation of the function of AT1 receptorassociated proteins has only recently begun, with Atrap
probably being the best characterized AT1 receptor accessory protein. Atrap is an 18-kDa protein with three putative transmembrane domains (534). It is expressed in
various organs, with the highest expression levels observed in the kidney, heart, and testes; on the other hand,
lower expression levels were found in the lung, liver,
spleen, and brain (180). In the kidney, Atrap was detected
by immunohistochemistry primarily in the tubular system,
where it partially colocalized with the AT1 receptors.
Little Atrap expression was detected in the renal vasculature, despite the marked expression of AT1 receptors,
implying a specific function of Atrap in modulating the
tubular effects of ANG II (893). The functional impact of
the Atrap-AT1 interaction has been assessed in several
studies. In vascular smooth muscle cells, the overexpression of Atrap resulted in enhanced internalization of the
AT1 receptor upon exposure to ANG II (174). Increased
AT1 receptor internalization was accompanied by marked
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inhibition of the angiotensin-induced proliferation of vascular smooth muscle cells (174). Similar results were
obtained for cardiomyocytes, in which the prohypertrophic effect of ANG II was reduced during the coexpression of Atrap and paralleled by reduced surface expression of AT1; once again, this indicates that Atrap promotes
the internalization of AT1 receptors (855). It should be
noted that the mutations in the COOH-terminal end of the
AT1 receptor, the putative binding site of Atrap, result in
a reduced internalization frequency of the AT1 receptor
(166, 329). Thus far, it remains unclear whether the negative effect of Atrap on the AT1 signaling is merely due to
a reduction of the AT1 surface localization or whether
Atrap also interferes with the AT1-dependent intracellular
signaling (517). A first attempt to address the in vivo
function of Atrap was recently made via the generation of
a transgenic mouse line that overexpresses Atrap under
the control of the CMV promoter (Atrap-Tg) (657). Atrap
mRNA expression in the heart, aorta, and femoral artery
was increased three- to fourfold compared with the wildtype controls (657). The arterial blood pressure and heart
rate were indistinguishable between Atrap-Tg and wildtype mice. However, the effect of cuff placement around
the femoral artery as an experimental approach to assess
vascular inflammation and remodeling was considerably
ameliorated in Atrap-Tg mice. Similarly, the progression
of heart hypertrophy after aortic banding was attenuated
in Atrap-Tg mice compared with wild-type mice, indicating that the overall effect of Atrap is attenuation of the
AT1-mediated signaling (657).
6. AT2 receptor function and signaling
The AT2 receptor is a seven-transmembrane domain
protein consisting of 363 amino acids with a molecular
mass of 41 kDa (604). AT2 and AT1 share 34% homology
(604). AT2 receptors are highly expressed in various tissues of the developing embryo, but expression declines
after birth (791, 792). The range of the AT2-dependent
functions is still not completely understood. Similarly, the
AT2-linked intracellular signaling events are still a matter
of intense research and appear to be far more diverse than
those of the AT1 receptor (for a comprehensive review,
see Ref. 825). However, there is growing evidence that
AT2-dependent signaling may antagonize the effects of
ANG II on AT1 receptors under various conditions. This
AT1-antagonizing effect of the AT2 receptor might be related, in part, to a direct interaction between the AT2 and
AT1 receptors. The AT2 receptors were shown to form
heterodimers with AT1 receptors, resulting in an attenuation of the AT1-mediated effects of ANG II (2). The
AT2-mediated effects of ANG II on vascular resistance
may serve as an example of how AT2 receptor activation
functionally counteracts the AT1 receptor. Thus, in contrast to AT1 receptor-deficient mice, the AT2 knockout
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645
mice were shown to exhibit increased arterial blood pressure (328, 370). Commensurate with the vasodilator effect
of AT2 activation, the infusion of ANG II under concomitant AT1 receptor inhibition resulted in a decrease in
arterial blood pressure in rats, which was dependent on
the intact NOS activity (116). Several other studies confirmed these findings and provided evidence that the ANG
II binding to AT2 results in enhanced formation of vasodilator agents like NO, prostanoids, and bradykinin, as
reviewed in detail elsewhere (951).
B. Renin/Pro-renin Receptor
Traditionally, the function of renin was thought to be
restricted to its enzymatic activity, i.e., cleavage of the
renin-substrate angiotensinogen. This assumption was
first challenged by the finding that human plasma contains
considerable amounts of the enzymatically inactive prorenin (542). This phenomenon raised the question as to
whether pro-renin in the circulation is somehow activated
or transformed into active renin and/or whether pro-renin
has a function that is entirely independent of the formation of enzymatically active renin, a function that might be
related to the binding of pro-renin (and/or renin) to receptors.
The first evidence for the existence of a renin/prorenin receptor was obtained by the finding that cultured
human mesangial cells are able to bind renin, which subsequently induced the synthesis and release of the plasminogen activator inhibitor-1 (626). In a similar study,
renin was shown to increase the expression of TGF-␤1
and extracellular matrix proteins upon binding to mesangial cells, an effect that was independent of the renin
activity (362). A few years after the discovery of the
ability of renin to bind to mesangial cells, the human
renin/pro-renin receptor was cloned (627). The renin/prorenin receptor is a single-transmembrane 45-kDa protein
consisting of 350 amino acids with no apparent homology
to known receptors. This novel receptor can bind both
pro-renin and renin (627). The binding of renin to its
receptor resulted in a fivefold increase in the catalytic
activity compared with renin in solution. The binding of
pro-renin to the receptor increased its enzymatic activity
from virtually zero to values comparable to those of active
renin in solution (for details on renin/pro-renin receptorindependent activation of pro-renin, see sect. IIIA1). Although the exact mechanism of pro-renin activation upon
receptor binding will require additional experimental efforts, it was suggested that pro-renin may employ its
handle region to bind to the receptor, which would eventually expose the active site of the enzyme (627). Furthermore, the binding of renin to its receptor initiated the
activation of the intracellular ERK1/ERK2 pathway independent of renin enzymatic activity (627). Thus the bind-
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ing of renin and/or pro-renin to its receptor boosts the
locally defined renin activity and is accompanied by intracellular signaling of the receptor-expressing cell.
These findings subsequently sparked interest in the
evaluation of possible clinical consequences of the renin/
pro-renin receptor binding in vivo. To address this issue,
a competitive inhibitor peptide was developed to prevent
pro-renin/renin from binding to its receptor (755). The
renin/pro-renin receptor inhibitor was used in rats during
endotoxin-induced uveitis, since ANG II was shown to be
crucially involved in the induction of ocular inflammation.
The inflammatory parameters were markedly alleviated
under the concomitant decoy peptide application (755).
The therapeutic benefit of the renin/pro-renin receptor
inhibitor appears to be substantial. The inhibition of renin/pro-renin receptor binding also markedly ameliorated
the progression of cardiac fibrosis in stroke-prone SHR
rats (368). In addition, the renin/pro-renin receptor inhibition was able to block MAPK activation and the development of glomerulosclerosis in a model of diabetic nephropathy (366). In a follow-up study in AT1a-deficient
mice, the authors suggested an ANG II-independent effect
that depended on pro-renin/renin receptor activation
(416). In addition, ACE inhibition was shown to be substantially less efficient than the application of the prorenin/renin receptor antagonist in preventing the development of diabetic nephropathy (416). With respect to the
effect of the renin/pro-renin receptor inhibitor on the
progression of cardiac fibrosis in SHR rats, the aforementioned results could not be confirmed without restrictions. Thus the prolonged infusion of the renin/pro-renin
receptor antagonist was shown in another study to somewhat reduce the left ventricular mass in SHR rats, but it
did not affect fibrotic cardiac remodeling, coronary hemodynamics, or left ventricular function (835). Similarly,
the beneficial effect of pro-renin/renin receptor inhibition
on renal function could not be confirmed in high-renin
models of hypertension like the two-kidney one-clip
model (543). In view of the outstanding relevance of the
initial findings regarding the beneficial effects of prorenin/renin receptor antagonism, future studies will be
required to substantiate the initial reports and to confirm
the results under modified experimental conditions.
In summary, a novel receptor type that binds renin
and pro-renin with equal affinity was discovered. Upon
receptor binding, a dual effect is observed. First, the
specific enzymatic activity of both renin and pro-renin is
substantially enhanced and, due to local renin/pro-renin
trapping, restricted to the local environment of the receptor-expressing cells. Therefore, the renin/pro-renin binding may provide a basis for the locally restricted renin
activity that might well exceed the magnitude of systemic
renin activity. Second, the binding of renin/pro-renin appears to initiate intracellular signaling in the receptorPhysiol Rev • VOL
expressing cell, and this effect might be of relevance
under pathophysiological conditions.
C. The ANG-(1–7)-ACE2-Mas Axis
New components and functions of the renin-angiotensin system are still being discovered. Within the last
decade, it has been recognized that the smaller peptide
fragments of the RAS, including ANG III, ANG IV, and
ANG-(1–7), also possess biological activity, but that their
plasma values are much lower than those of ANG II, with
the exception of ANG-(1–7) (321, 680). The identification
of the ACE homolog ACE2, an important enzyme for the
generation of ANG-(1–7), and of the G protein-coupled
receptor Mas, which is encoded by the Mas protooncogene, as a receptor for ANG-(1–7), broadened our knowledge of the RAS towards a system containing at least two
cascades, with the ACE2-ANG-(1–7)-Mas axis likely acting
as a counterregulatory portion of the classical RAS axis.
The increasing interest in this area of research has been
documented by several reviews, in which the interested
reader can obtain a more comprehensive overview (177,
223, 224, 424, 449, 498, 713, 752, 907).
1. Function of Ang-(1–7) and expression of ACE2 in
the cardiovascular system
ANG-(1–7) can be formed from ANG I and ANG II by
the action of ACE, ACE2, and several other enzymes,
including neprilysin (NEP) and prolyl oligopeptidase
(POP) (222), whereas ACE is the main enzyme responsible for the conversion of ANG I into ANG II. The carboxypeptidase ACE2 cleaves ANG II into ANG-(1–7)
(912). Furthermore, ACE2 forms ANG-(1–9) from ANG I,
which can then be converted into ANG-(1–7) by ACE
(202). However, the preferable physiological substrate for
ACE2 seems to be ANG II (878, 912). ANG-(1–7) is subsequently metabolized into the inactive fragment ANG(1–5) by the activity of ACE (16, 139, 186). In addition,
ACE2 is also capable of metabolizing other peptides, such
as apelin-13, des-Arg[9]-[bradykinin], ␤-casomorphin-(1–
7), dynorphin A-(1–13), ghrelin, and neurotensin-(1–11)
(202, 912). The half-life of the heptapeptide ANG-(1–7) is
very short (several seconds) in rats (962), and ACE inhibitors, which inhibit the metabolism of ANG-(1–7) into
ANG-(1–5), clearly increase the half-life of ANG-(1–7)
(962). The 805-amino acid enzyme ACE2 is a monocarboxypeptidase with one active site domain that shares
⬃42% homology with the active site of ACE (202, 878,
912). ACE2 gene expression has been found in the heart,
kidney, and testes and, to a lower extent, in the liver, lung,
small intestine, and brain of humans and rodents (259,
303, 451). ACE2 is an ectoenzyme, although a soluble
active form has also been described in plasma and urine
(790, 939).
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The first biological activities of ANG-(1–7) to be described were the demonstration of AVP release from the
hypothalamo-neurohypophysial system and the decrease
of arterial blood pressure after microinjection of low
doses of ANG-(1–7) into the dorsal medulla of rats (111,
757). Further studies have demonstrated immunostaining
of ANG-(1–7) in central regions related to the synthesis
and release of vasopressin (79, 110, 467). Subsequent
studies have shown that ANG-(1–7) is involved in the
baroreflex control of the heart rate at the nucleus tractus
solitarii (67, 112, 143, 645, 742), enhances the long-term
potentiation in the hippocampus (330), and contributes to
the maintenance of sympathetic nerve activity in the neurons of the paraventricular hypothalamic nucleus (805).
In line with these observations, ACE2 expression has
been reported in various cardiovascular regulatory brain
areas (203, 742). ACE2 protein expression was found to
be lower in the rostral ventrolateral medulla of SHR compared with normotensive Wistar-Kyoto rats (WKY), and
vascular or central overexpression of ACE2 was found to
decrease blood pressure in SHR (724, 965).
With regard to the heart, it has been found that
ANG-(1–7) evokes antiarrhythmogenic effects (226, 751),
dilates the coronary arteries (87), increases coronary
blood flow (123, 124), and affects the cardiac contractility
(225, 750). The cardiac expression of ACE2 has been
localized to endothelial cells and smooth muscle cells
from the intramyocardial vessels and myocytes (104, 202,
878). ACE2-deficient mice show reduced cardiac contractility, a decrease in aortic and ventricular pressure, and a
thinning of the left ventricular wall. These changes progressed with age and were more prominent in male mice.
The hearts of ACE2 knockout mice exhibited enhanced
ANG II levels and increased levels of hypoxia-inducible
genes (170). However, these effects seem to be dependent
on the background of the ACE2-deficient mice (288). Increased cardiac ACE2 expression and activity have been
found in failing human and rat hearts following arterial
ligation and AT1-receptor antagonism (104, 223, 378). In
agreement with these findings, ANG-(1–7) exerts a protective role for the heart in several animal models by
decreasing or preventing the development of cardiac hypertrophy and fibrosis (68, 281, 282, 533, 751). This effect
seems to be independent of blood pressure reduction
(281, 282). In addition, it has been shown that ANG-(1–7)
initiates antifibrotic and antitrophic effects in cardiac fibroblasts and inhibits growth in rat cardiomyocytes (386,
847). Moreover, ANG-(1–7) has been reported to decrease
cardiac ANG II levels (577) and to attenuate the diabetesinduced cardiovascular dysfunction (69), as well as hypertension-induced cardiac remodeling (580).
Vascular endothelial cells can form ANG-(1–7) via
the activity of ACE2 (104, 749) and are also an important
target for the action of ANG-(1–7). The vasodilatory effect
of ANG-(1–7) depends on an intact endothelium (503),
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where ANG-(1–7) can induce the release of NO via eNOS
(744). In addition to its effect on NO release, ANG-(1–7)
stimulates the release of prostanoids from endothelial and
vascular smooth muscle cells (393, 394, 613). Moreover,
ANG-(1–7) seems to potentiate the vasodilatory effect of
bradykinin (87, 519, 675, 676) and attenuate the vasoconstrictor effect of ANG II (895). However, vasoconstriction
in response to ANG-(1–7) has also been reported (1, 656).
In addition, ANG-(1–7) also acts on vascular smooth muscle cells, where it inhibits cell growth (233, 846). More
recently, ANG-(1–7) has been proposed to attenuate atherosclerotic plaques in animals (201, 540).
The pulmonary ACE2 expression has been described
for type I and type II alveolar epithelial cells, bronchiolar
epithelial cells, endothelial cells, and arterial smooth muscle cells (303, 372, 471). ACE2 expression decreases with
aging in rat lungs and is higher in old female rats compared with old male rats. The ACE2-deficient mice do not
show any pulmonary abnormalities (170). However, ACE2
deletion worsens the severe acute lung injury induced by
acid aspiration or sepsis, and the injection of recombinant
human ACE2 attenuates the acute lung failure in the
ACE2 knockout as well as wild-type mice (372). In addition, ACE2 is a well-described receptor for the severe
acute respiratory syndrome coronavirus (SARS-CoV) and
for the human coronavirus-NL63 (348, 515). The SARSCoV infection can be attenuated by soluble ACE2 molecules, ACE2 antibodies, and the genetic deletion of ACE2
(304, 472, 515).
Several studies have demonstrated that the kidney is
an additional target for the action of ANG-(1–7). ANG(1–7) injection has been shown to increase the sodium
and water excretion, as well as the GFR, without affecting
the renovascular resistance in isolated perfused rat kidneys and in anesthetized animals (189, 899). Subsequent
studies have found that ANG-(1–7) modulates the activity
of Na⫹-K⫹-ATPase in the basolateral membranes of kidney proximal tubules (121, 305). In addition, ANG-(1–7)
has been reported to stimulate the arachidonic acid release from isolated proximal tubules (26), and the inhibition of prostaglandin release by COX inhibition attenuates
the ANG-(1–7)-induced increase in urine flow and sodium
excretion (336). ANG-(1–7) has also been shown to cause
afferent arteriolar vasodilation and to antagonize the vasoconstrictor effects of ANG II (32). The intrarenal blockade of ANG-(1–7) causes a decrease in GFR, renal plasma
flow, and sodium excretion in rats with increased activity
of renal RAS (100). However, ANG-(1–7) also induces
antidiuresis in water-loaded rodents (748) and increases
renal tubular sodium reabsorption in rats (101).
ACE2 gene expression has been described for glomeruli, vasa recta, and all nephron segments except the
mTAL (514). Relatively high amounts of ACE2 were detected in the apical brush-border membrane of proximal
tubule epithelia, where it colocalized with ACE (514).
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Within the glomerulus, ACE2 is localized in podocytes
and, to a smaller extent, in the mesangial cells (974). The
increased renal ANG-(1–7) levels and renal expression of
ACE2 have been found during pregnancy (88, 410) and in
response to ACE inhibition or ANG-II-AT1 receptor antagonism (404, 876). Renal ACE2 expression was found to be
lower in adult SHR compared with age-matched WKY rats
during lipopolysaccharide-induced acute renal failure and
in several models of diabetic kidney injury (287, 875, 876,
974, 988). Several findings have suggested a protective
role for the ACE2-ANG-(1–7)-Mas axis during diabetic
nephropathy: 1) ACE2 gene deletion and pharmacological
ACE2 inhibition with the ACE2 inhibitor MLN-4760
worsen the development of glomerular injury in diabetic
mice (819, 957), 2) treatment with ANG-(1–7) or the Mas
receptor agonist AVE0991 ameliorates diabetes-induced
renal and cardiovascular dysfunction (69, 70, 210),
3) attenuation of diabetic renal injury by ACE inhibition is
paralleled by the increased ACE2 expression (876), and
4) increased ACE2 expression in streptozotocin-induced
diabetic mice has been reported (960). However, ACE2
polymorphisms and diabetic nephropathy do not seem to
be associated in humans (242). A recent study reported
that loss of the ACE2 gene leads to the development of
ANG II-dependent glomerular injury in male mice, but not
in female mice. Moreover, these authors found that the
greater degree of glomerulosclerosis and proteinuria was
attenuated by ANG II-AT1 receptor inhibition (661). In
humans, the de novo expression of ACE2 in biopsies of
patients with renal diseases and an increased ACE to
ACE2 ratio in subjects with hypertension have been reported (508, 930).
2. Mas receptor
The existence of a receptor for ANG-(1–7) was initially suggested by pharmacological studies using ANG(1–7) antagonists (848). The orphan heterotrimeric guanine nucleotide-binding protein-coupled receptor, i.e., the
Mas receptor, was later suggested to be the functional
binding partner for ANG-(1–7) (510). The Mas gene encodes for a G protein-coupled receptor and was originally
detected in vivo by tumorigenic properties originating
from the rearrangement of its 5⬘ region flanking a protooncogene, due to its tumorigenicity (708, 979). The
genetic deletion of the Mas receptor has been shown to
eliminate the binding of ANG-(1–7) to mouse renal cells,
leading to impaired cardiac and renal function and to
attenuation of the vasodilator effects of ANG-(1–7) (753)
(Fig. 7). The Mas gene is expressed in the brain, testes,
kidney, and heart (391, 581, 978). Within the central nervous system, the Mas receptor expression has been found
in various regions, including the cardiovascular regulatory areas (58). In agreement with the activities described
for ANG-(1–7), Mas-deficient mice exhibit increased
Physiol Rev • VOL
FIG. 7. Components of the renin-angiotensin I-Mas axis. For details,
please see text.
blood pressure, impaired endothelial function, decreased
NO production, and decreased endothelial NO synthase
expression (679, 961). In line with the cardioprotective
effects of ANG-(1–7), the genetic deletion of the Mas
receptor impairs heart function and changes the extracellular matrix to a profibrotic state (750). In addition, the
genetic deletion of the Mas receptor leads to changes in
glucose and lipid metabolism (754), erectile function
(176), heart function (123, 750), and brain function (330).
The intracellular signal transduction mechanisms that follow the activation of the Mas receptor are only poorly
understood. ANG-(1–7) stimulates the phosphorylation of
Janus kinase 2 (JAK2) and insulin receptor substrate
(IRS)-1 in the rat heart in vivo (266). Mas receptor activation leads to an increase in the NO production via the
phosphorylation of eNOS, which involves the activation
of the phosphatidylinositol 3-kinase-dependent Akt phosphorylation (192, 744). Furthermore, the inhibition of
MAPK phosphorylation upon activation of the Mas receptor has been described (830, 847). In addition, the Mas
deficiency impairs Ca2⫹ management in cardiomyocytes
(192). In the Mas-transfected CHO and COS cells, ANG(1–7) stimulated the release of arachidonic acid (753).
It should be noted, however, that some studies have
shown that ANG-(1–7) can also bind to the AT1 and AT2
receptors, although rather high concentrations of ANG(1–7) are necessary (552, 730, 931). In addition, the exis-
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PHYSIOLOGY OF KIDNEY RENIN
tence of another ANG-(1–7) receptor has been suggested
(806), and an interaction between the different angiotensin receptors has been proposed (124, 460).
VII. CONCLUSION
Despite the long-standing awareness of renin production and secretion, our knowledge of its regulation and
(patho)physiological relevance has steadily increased
during the last few years. We have begun to understand
the fundamental properties of renin gene regulation: in
particular, its stimulation by the cAMP pathway and
(mostly) inhibitory modulation by specific hormones and
cytokines. We have improved our knowledge of the development, cell biology, and function of renin-producing
cells in the kidney, commonly referred to as JG cells. The
discovery of the functional relevance of gap junctions in
JG cells has revealed novel and promising insights into
the cell biology of renin-producing cells. Although the
cAMP signaling pathway is known as a very powerful
stimulator of renin secretion, the detailed mechanisms of
renin release are still obscure and await further clarification. The mysterious “calcium paradox,” referring to the
inhibitory effect of calcium on secretion in renin-producing cells, may have found at least a partial explanation in
the existence of calcium-inhibitable adenylyl cyclases in
JG cells. ATP, NO, and prostanoids have emerged as
powerful signals that mediate the local control of renin
secretion and synthesis. Furthermore, the list of hormones that act directly on JG cells has been substantially
enlarged. ANG II, the classic biological effector of the
RAS, has been shown to act through different receptors
that mediate antagonistic effects. Moreover, ANG II is
probably not the only biological mediator of the reninangiotensin system because (pro)renin and ANG-(1–7)
were also found to exert direct and distinct biological
effects. The knowledge about kidney renin is certainly not
yet complete, although 100 years have passed since its
discovery. We may therefore anticipate with interest the
novel findings about kidney renin that are expected in the
upcoming years.
ACKNOWLEDGMENTS
Address for reprint requests and other correspondence:
A. Kurtz, Institute of Physiology, Univ. of Regensburg,
D-93040 Regensburg, Germany (e-mail: armin.kurtz@vkl.uniregensburg.de).
GRANTS
The authors’ work was financially supported by Deutsche
Forschungsgemeinschaft Grant SFB 699.
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