Renin-Angiotensin System

Afferent

Macula
Densa

JG Apparatus

Efferent
 Factors Affecting Renin Release

Increased By Decreased By
•Na+, water
•Arterial BP retention
•BP in Glomerular Renin
•BP
Vessels Release
•Activation of AT1
•Loss of Na+, receptors (short
water loop negative feed
•Sympathetic back)
activity
•Renin- synthesized, stored and released by exocytosis
into renal artery circulation by JG cells
•Both renin and prorenin are stored in the JG cells
•Prorenin is converted to renin by proteolytic enzymes-
proconvertase I or cathepsin B
•Concentration of prorenin is about 10 times higher than
renin in circulating blood
•Renin converts angiotensinogen to angiotensin I which
is then converted to angiotensin II by Angiotensin
Converting Enzyme (ACE)
•Angiotensin II is the active form of the enzyme
 Control of Renin Secretion
•Macula densa pathway
•Intrarenal baroreceptor pathway
•-receptor pathway
 Macula densa pathway
•Specialized columnar epithelial cells in thick
ascending limb of the nephron
•Lies between the afferent and efferent arterioles
adjacent to the JG apparatus
•Reabsorption of NaCl occurs by macula densa cells
•Changes in NaCl reabsorption modify renin release
from the JG cells
•Increase in NaCl flux causes inhibition of renin
release while decrease causes increased renin release
•ATP, adenosine & PG modulate this pathway
 Macula densa- control of renin release

AngII
ATP
Na+ +
Na+-K+-2Cl- Na -ve Feed back
+
symporter 2Cl- K+ AT1 NE release
K+ 1
ADP P2Y
—
(Gq-PLC-IP3 -
Tubular Adenosine Ca2+ PG

End nNOS A1 (-) (+)

Adenosine Renin Release
NO Receptor

COX-2 PG

Macula densa JG Cell

•In macula densa, regulation is mainly by concentration
of Cl- concentration rather than Na+ concentration
•Concentration of Na+ in tubular lumen is usually higher
than required for saturating the symporter due to which
changes in levels of Na+ do not have much effect on
macula densa
•Cl- concentrations required for saturation of the
symporter are high due to which changes in its
concentration mainly effect macula densa mediated
renin release
•Renin release control: mechanism II- intrarenal
baroreceptor pathway
• in BP or renal perfusion pressure in preglomerular
vessels inhibits renin release and vice versa
•May be mediated by stretch receptors in arterial walls
or/and by PG synthesis
•Mechanism III: via 1 receptors on JG cells
•Increased renin secretion enhances formation of
angiotensin II which is responsible for short loop
negative feed back
•Other factors in negative feed back:
Activating high pressure baroreceptors and thereby
reducing renal sympathetic tone- k/a long loop negative
feed back
Increasing pressure in the preglomerular vessels
Reducing NaCl reabsorption from the proximal tubule
(pressure natriuresis) thereby reducing delivery of NaCl
to macula densa which reduces renin release
Physiological factors modifying renin release:
•Systemic blood pressure
•Dietary salt intake
•Pharmacological agents-
NSAIDs- inhibit PG synthesis   renin release
Loop diuretics decrease BP and increase NaCl
reabsorption causing increased renin release
ACE inhibitors, ARBs, renin inhibitors
Centrally acting sympatholytic agents and -blockers
decrease renin secretion by reducing -receptor
activation
 ACE
•It is a glycoprotein
•It is nonspecific enzyme that catalyzes diverse amino
acids
•It is identical to Kinase II that inactivates bradykinin and
other potent vasodilator peptides
•ACE is present in the vascular endothelium which is
responsible for rapid conversion of Ang I to Ang II
•ACE2: present in human body- carboxypeptidase
•It cleaves one amino acid residue from Ang I to convert
it to Ang (1-9) and Ang II to Ang (1-7)
•Ang (1-7) binds to Mas receptors and elicits vasodilator
and non-proliferative responses
•ACE2 has 400 fold greater affinity for AngII than AngI
•ACE2 is not inhibited by standard ACE inhibitors used
•It has no effect on bradykinin
•Physiological significance uncertain
•May act a a counter-regulatory mechanism to oppose
effects of ACE
•It regulates effects of Ang II by converting it to Ang (2-8)
also called Ang III
•Ang IV (3-8) is formed from Ang III
•Ang I has is less than 1% potent than Ang II
•Angiotensinogen is formed in the liver
•Major site for conversion of Ang I to Ang II is the lung
•Reason: because it has a large number of capillaries
and ACE is present in the endothelial cells of the
capillaries
•Other sites: other blood vessels specially of kidney
•Angiotensinages are diverse group of enzymes like
aminopeptidases, endopeptidases, carboxypeptidases
and other peptidases that degrade and inactivate
angiotensin
•They are non-specific enzymes
 Local (Tissue) Renin-Angiotensin System
•Important for its role in hypertrophy, inflammation,
remodelling and apoptosis
•Binding of renin or pro-renin to pro-renin receptors
located on cell surface
•Present in many tissues like brain, pituitary blood
vessels, heart, kidney, adrenal glands
•Extrinsic local RAS: in vascular endothelium of these
tissues
•Intrinsic local RAS: tissues having mRNA expression
•Number of enzymes that act as alternative pathway for
conversion of angiotensinogen to AngI or directly to
AngII
•Enzymes are: cathepsin, tonin, cathepsin G,
chymostatin sensitiveAngII generating enzyme and
heart chymase
•Angiotensin receptors:two types-
AT1 and AT2
Most effects of AngII are mediated by AT1 receptors
Role of AT22 receptors not well defined
May counterbalance many effects of AT1 activation
 Functions of RAS
•Effects of AngII on CVS include:
Rapid pressor respone-  peripheral resistance
Slow pressor response- via decrease in renal excretion
and production of endothelin-1
Vascular and cardiac hypertrophy and remodeling
Rapid pressor response:
•AT1 receptors are located in the vascular smooth muscle
cells
•Ang II activates these receptors and constricts the
precapillary arterioles and to a lesser extent the
postcapillary venules
•It stimulates the Gq-PLC-IP3-Ca2+ pathway
•Vasoconstriction is maximum in kidneys, lesser in
splanchnic.
•Weak vasoconstrictor action in brain, lung and skeletal
muscles
Other contributing factors are:
•Enhancement of peripheral NE neurotransmission by:
Inhibiting reuptake of NE into nerve terminals
Enhancing vascular response to NE
High concentrations of Ang II stimulate ganglion
cells directly
•CNS Effects:
Increase in central sympathetic outflow
Attenuation of baroreceptor mediated reductions in
sympathetic discharge from brain
•Brain contains all components of RAS
•Brain is affected by both circulating AngII and AngII
formed within the brain
•Action of AngII on brain causes:
Increased central sympathetic tone
Dipsogenic effect (thirst)
•Release of catecholamines from adrenal medulla: AngII
depolarises the chromaffin cells of adrenal medulla and
causes release of adrenaline
Slow Pressor Response:
•Produced by effect on the kidneys
•AngII:
Reduces urinary excretion of Na+ and water
Increases excretion of K+
Stimulates Na+/H+ exchange in proximal tubule due to
which Na+, Cl- and bicarbonate reabsorption increases
Increases expression of Na+-glucose symporter in
proximal tubule
Directly stimulates Na+-K+-2Cl- symporter in thick
ascending limb
•Proximal tubule secretes angiotensinogen and the
connecting tubule secretes renin
•Paracrine tubular RAS? Functions?
•AngII stimulates zona glomerulosa of adrenal cortex to
increase the synthesis and secretion of aldosterone
•Also auguments its response to other stimuli like
ACTH, K+
•Aldosterone acts on distal and collecting tubules to
cause retention of Na+ and excretion of K+ and H+
•Stimulatory effect of AngII on aldosterone secretion
depends on plasma concentrations of Na+ and K+
•Release of aldosterone is enhanced in cases of
hyponatremia or hyperkalemia and vice versa
•Effect on glomerular filtrate:
Constriction of afferent arterioles reduces
intraglomerular pressor and tends to reduce GFR
Contraction of mesangial cells decreases the capillary
surface area within the glomerulous and tends to
decrease GFR
Constriction of efferent arterioles increases the
intraglomerular pressor and tends to increase GFR
Normally, GFR is slightly reduced by AngII
•Vascular and cardiac hypertrophy and remodeling:
Cells involved- vascular smooth muscle cells, cardiac
myocytes and fibroblasts
Stimulates migration, proliferation and hypertrophy of
vascular smooth muscle cells
Increases extracellular matrix production by vascular
smooth muscle cells
Causes hypertrophy of cardiac myocytes
Increases extracellular matrix production by cardiac
fibroblasts
Effect on heart:
•Increases cardiac contractility directly by opening of
voltage gated Ca2+ channels in cardiac myocyte
•Increases cardiac rate indirectly by increasing central
sympathetic tone
•Increases adrenal release of catecholamines
•Facilitates adrenergic neurotransmission
•Rapid rise in BP causes baroreceptor stimulation-
decrease in central sympathetic tone and increased vagal
tone
•Net effect-uncertain
 Inhibitors of RAS
•ACE inhibitors (ACEIs)
•Angiotensin receptor blockers (ARBs)
•Direct renin inhibitors (DRIs)