Renal Physiology II:
JA; DCT; Aldosterone
DCOM MS LSCI-510
Principles of Physiology
L25 Renal Physiology II
Distal Convoluted Tubule
April 15, 2020
Dr. Stan Kunigelis
Stan.Kunigelis@LMUnet.edu
Office: DCOM 217 (6818)
IAC Lab: Hamilton 120 (6385)
Learning Objectives …
1) Describe the anatomical components of the
Juxtaglomerular Apparatus and their functions.
2) Distinguish the secretions of the macula densa,
mesangial cells, and juxtaglomerular cells.
3) Describe the role of juxtaglomerular cells in the
activation of renin-angiotensin-aldosterone
system.
4) List the actions of aldosterone on the distal
convoluted tubule to regulate blood pressure.
5) Describe the mechanism of unfiltered waste
secretion into the distal convoluted tubule.
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Distal Convoluted Tubule:
Renin-Angiotensin-Aldosterone
System
Juxtaglomerular Apparatus
The Juxtaglomerular Apparatus (JA) comprises the macula densa (tubular origin)
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and granular cells (vascular origin).
JA regulates both glomerular filtration rate (local autoregulation) and secretes
the enzyme renin in response to systemic hypotension.
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Macula Densa
• The macula densa is a
sensor formed by the
wall cells of the earliest
section of the distal
convoluted tubule that
1o abuts the afferent
and 2o the efferent
arterioles feeding the
glomerulus.
• Technically, it is the
earliest portion of the
distal convoluted tubule
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Macula Densa
• Tubular Origin
• the macula densa
functions as a sensor,
monitoring tubular fluid
flow rate through a single
nephron
• should the glomerular
filtration rate (GFR)
deviate from that
expected* for a given
arterial pressure, then the
macula densa releases
vasoactive compounds to
maintain a constant GFR
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* Recall deviations from homeostatic set points!
Macula Densa: GFR
• Tubular Origin
• for example, if the GFR becomes too high the
body risks the loss of water and ions which can
cause hypotension, a drop in systemic blood
pressure
• therefore, the macula densa responds by
releasing vasoconstrictors which decrease the
GFR through that one nephron (note that this is
a local autoregulatory response)
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Macula Densa: GFR
• Tubular Origin
• If the macula densa detects that the GFR is too
low through that one nephron, the body is at risk
of accumulating wastes, experiencing water and
electrolyte imbalance which could lead to
systemic hypertension
• therefore, the macula densa releases a
vasodilator to increase GFR through that one
nephron (once again, this is local autoregulation)
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Macula Densa
• these autoregulatory
mechanisms allow GFR to
remain constant between a
MAP of 80-180 mmHg
• outside of this normal range
of MAP, GFR changes
dramatically with blood
pressure
• keep in mind that this
autoregulation can be easily
overridden by the
sympathetic nervous
system and vasoactive
compounds like angiotensin
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Granular = Juxtaglomerular Cells
• Vascular Origin
• the macula densa (remember
that this is part of the distal
tubule) contacts the afferent
/efferent arterioles just as they
enter/leave the glomerulus
• here, the wall of the afferent
and efferent arterioles contains
secretory granular cells
(=juxtaglomerular (modified
smooth muscle =
myoepithelioid) cells)
• There are more granular cells
surrounding the afferent (input)
than efferent (output) arteriole
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Granular = Juxtaglomerular Cells
• Vascular Origin
• granular cells
– i) are pressure sensitive, functioning as an intrarenal
baroreceptor
– ii) secrete the enzyme renin
• activation of the renin-angiotensin-aldosterone
system in response to systemic hypotension leads
to vasoconstriction (angiotensin II) and the
reabsorption of Na+, loss of K+ and H+
(aldosterone), which leads to a net uptake of renal
water to expand the extracellular fluid volume which
increases systemic blood pressure (remember that
NaCl provides 90% of the osmotic force to attract
and hold water)
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Granular = Juxtaglomerular Cells
As such, JA is involved in autoregulation of
1. Flow Rate: GFR through a single nephron
(macula densa), and
2. BP: releases renin in response to
hypotension (granular cells), to produce
angiotensin II, the most potent
vasoconstrictor in the body
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Don’t confuse
renin with rennin!
1) ACE-Is also block
bradykinin degredation
prolonging vasodilation
to further decrease
BP.
2) Dry cough side effect
of ACE-Is.
3) ACE RBs has no
influence on
bradykinin.
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• The renin-angiotensin-aldosterone system plays an
important role in regulating blood volume, arterial pressure,
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and cardiac and vascular function.
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Note that ACE inhibitors or ARBs can be used in the control of hypertension.
The corona virus responsible for the 2020 pandemic is believed to gain entrance via lung ACE receptors!
ALDOSTERONE
-aldosterone is a mineralcorticoid produced by the adrenal glands
-aldosterone release can come about by one of two distinct mechanisms
1. the adrenal gland has receptors which monitor
the [K+] ECF
– if K levels become too high, aldosterone is released
into the general circulation
2. adrenal gland release of aldosterone is stimulated
by angiotensin II via JA renin
-in response to hypotension, the granular/ juxtaglomerular
cells of the afferent and efferent arterioles (supplying the
glomerulus) release renin
-renin leads to the activation of angiotensin II which
stimulates the release of aldosterone from the adrenal
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cortex
• aldosterone acts upon the distal convoluted tubule of the kidney
nephron to:
a) activates the Na+/K+-ATPase
b) increases K permeability (activation of existing channels)
c) increases Na permeability (stimulates the synthesis of
new Na channels)
• as we saw in 1) the action of aldosterone is to cause a net
reabsorption of Na and a net secretion of K and H
• this results in restored blood pressure and the loss of excess K
• Note: The renal corpuscle (glomerulus and Bowman's capsule) is
freely permeable to both Na+ and K+. However, the body's strategies
for recovering these ions is quite different.
– The body reabsorbs only the Na that is needed, the rest is lost with urine.
– In contrast, the body reabsorbs all filtered K, then actively secretes any excess.
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Let’s Look At This in Greater Detail
•
aldosterone acts on the distal convoluted tubule to
carry out the following:
a) activate a Na+/K+-ATPase (serosal (blood)
surface) which secretes K+ to the tubular fluid
(urine) and reabsorbs Na+
–
–
–
–
this provides net Na reabsorption and K secretion
since the ATPase is electrogenic, 3Na+ are reabsorbed for
every 2K+ secreted
in order to maintain charge neutrality H+ is also secreted
(3Na/2K, 1H)
as such, aldosterone leads to the loss of H+ which acidifies
the urine
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Let’s Look At This in Greater Detail
•
aldosterone acts on the distal convoluted
tubule to carry out the following:
b) increased K permeability (lumenal
surface) of the distal convoluted tubule
wall (aldosterone activated, ATP
dependent K channels) which makes it
easier to lose excess K
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Let’s Look At This in Greater Detail
•
aldosterone acts on the distal convoluted
tubule to carry out the following:
c) stimulates the de novo synthesis of Na
channel proteins (i.e., subunits) which
are inserted into the lumenal surface of
the distal convoluted tubule to facilitate
the uptake of Na
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Remember that the body filters all Na and reabsorbs only what is needed.
• remember that only 8% of the filtered Na is
actively reabsorbed in the distal
convoluted tubule
– 67% in proximal convoluted tubule
– 25% in loop of Henle
• however, this 8% of total Na has
the greatest influence on
systemic MAP
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Aldosterone
1. activates Na/K-ATPase,
2. ρK (existing channels),
3. ρNa (new channel formation).
Na+
Serosal Surface
K+
K+
Na+
Tubular Surface
DCT Wall
Tubular Fluid
DCT Wall
Cell
3Na reabsorbed for every 2K and 1H secreted
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Juxtaglomerular Apparatus
Macula Densa
Granular Cells
• Tubular origin
• Earliest region of DCT
monitors tubular fluid flow
rate through a single nephron
• Releases vasodilators if
GFR
• Releases vasoconstrictors if
GFR
• Vasoactive compounds
diffuse to afferent arterial
to alter GFR to that one
nephron  local
• Vascular origin
• Pressure sensitive intrarenal
baroreceptors
• Secretory cells present in the
wall of the afferent and
efferent arterioles release
renin in response to
hypotension
• Activates the reninangiotensin-aldosterone
system global response
autoregulatory response
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Diuretics
Diuretics are drugs that increase urine production,
relieving excess fluid buildup in body tissues. Diuretics
are used to treat high blood pressure, lung disease,
premenstrual syndrome, and other conditions.
1. Loop diuretics exert their action on the sodium reabsorption
mechanism of the thick ascending limb of the loop of Henle, resulting in excretion
of urine isotonic with plasma.
2. Thiazides a group of synthetic compounds that decrease
reabsorption of sodium by the kidney and thereby increase loss of water
and sodium; they enhance excretion of sodium and chloride equally
3. Osmotic diuretics are a group of low molecular weight substances
that can remain in high concentrations in renal tubules contributing to osmolality
of glomerular filtrate.
4. Potassium-sparing diuretics
those block the exchange of
sodium for potassium and hydrogen ions in the distal tubule, increasing sodium
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and chloride excretion without increasing potassium excretion.
FYI
Examples
Mechanism
-
Ethanol, Water
inhibits vasopressin secretion
ACIDIFYING SALTS
CaCl2, NH4Cl
ARGININE VASOPRESSIN
amphotericin B, lithium citrate
inhibit vasopressin's action
AQUARETICS
Goldenrod, Juniper
Increases blood flow in kidneys
NA-H EXCHANGER ANTAGONISTS
dopamine
promote Na+ excretion
proximal tubule
CARBONIC ANHYDRASE INHIBITORS
Acetazolamide, dorzolamide
inhibit H+ secretion, resultant
promotion of Na+ and K+ excretion
proximal tubule
LOOP DIURETICS
Bumetanide, ethacrynic acid,
furosemide,, torsemide
inhibit the Na-K-2Cl symporter
medullary thick ascending limb
OSMOTIC DIURETICS
glucose (especially in
uncontrolled diabetes), mannitol
promote osmotic diuresis
proximal tubule, descending limb
POTASSIUM-SPARING DIURETICS
amiloride, spironolactone,
triamterene, potassium
canrenoate.
inhibition of Na+/K+ exchanger:
Spironolactone inhibits aldosterone
action, Amiloride inhibits epithelial
sodium channels
cortical collecting ducts
THIAZIDES
bendroflumethiazide,
hydrochlorothiazide
inhibit reabsorption by Na+/Clsymporter
distal convoluted tubules
XANTHINES
Caffeine, theophylline,
theobromine
inhibit reabsorption of Na+,
increase glomerular filtration rate
tubules
RECEPTOR 2 ANTAGONISTS
Location
collecting duct
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Kidney Disease
• Hereditary Disorders
– polycystic kidney disease*,
– Alport's syndrome,
•
•
•
•
•
glomerulonephritis,
endstage kidney disease,
hearing loss,
may affect the eyes.
blood in the urine (hematuria).
– hereditary nephritis,
– primary hyperoxaluria and
– cystinuria.
• Congenital Disease
– malformation of the
genitourinary tract, leading
to obstruction, infection,
and/or destruction of kidney
tissue.
• Acquired Kidney Disease
– Kidney Stones
– Nephrotic Syndrome
• large protein loss in the urine
[frequently in association with
low blood protein (albumin)
levels, an elevated blood
cholesterol and severe
retention of body fluid,
causing swelling (edema)].
– Long-standing High Blood
Pressure (hypertension)
– Diabetes
– Drugs and Toxins
• Certain medications, toxins,
pesticides and "street" drugs
(i.e., heroin) can also produce
kidney damage.
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*PCKD is associated with increased risk of intracranial aneurysms. 53-70yo life expectancy. 1/1K incidence.
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