Mechanism

of Action of
RAAS

Renin Angiotensin Aldosterone

System
-a presentation by SRISTI &
VINITA
RENIN RELEASE
-
Within the afferent arterioles of the kidney, specialized cells called juxtaglomerular (JG) cells contain
prorenin. While prorenin is secreted constitutively in its inactive form, activation of JG cells causes the
cleavage of prorenin to renin.

Triggers for renin release-

a) Decreased BLOOD PRESSURE
b) Beta-activation of SYMPATHETIC NERVOUS SYSTEM
c) Macula Densa cells in DCT ( Distal Convoluted Tubule ) of Kidneys senses less Sodium in the fluid
passing through it. Hence , prostaglandin releases and act as a local messenger which ultimately
triggers the release of renin.
 once renin has been released into the blood, it can act on its
target, angiotensinogen. Angiotensinogen is produced in the
liver and is found continuously circulating in the plasma.

Renin then acts to cleave angiotensinogen into angiotensin I.

Angiotensin I is physiologically inactive but acts as a
CONTINUE precursor for angiotensin II.

D… The conversion of angiotensin I to angiotensin II is catalyzed

by an enzyme called angiotensin converting enzyme (ACE).
(ACE is found primarily in the vascular endothelium of the
lungs and kidneys).
After angiotensin I is converted to angiotensin II, it has effects
on the kidney, adrenal cortex, arterioles ,sympathetic nervous
system and brain by binding to angiotensin II type I (AT) and
type II (AT) receptors.
 Binding of Angiotensin II

Angiotensin II exerts its action by binding to various receptors throughout the body. It binds to one of two
G-protein coupled receptors, the AT1 and AT2 receptors. Most actions occur via the AT1 receptor.

Much less is known about the physiological role of AT2 receptors.

THE AT1 RECEPTOR

The AT1 receptor reportedly interacts with various G proteins and is coupled to one of the two heteromeric G proteins:
Gqα or Giα .

Ang II binding to specific sites of the extracellular and membrane-spanning portions of the AT1 receptor releases the α subunit
of the G protein and subsequently activates phospholipase C via Gq or inhibits adenylate cyclase via Gi.

Phospholipase C activation generates 1,4,5-inositol triphosphate and diacylglycerol, with subsequent activation of protein
kinase C and an increase in intracellular (Ca2+) via L-type (Ca2+) channels .

The rise in intracellular (Ca2+) is accompanied by typical AT1 receptor-associated responses such as vasoconstriction, renal
salt and water retention, aldosterone and vasopressin release, effects on glomerular filtration rate, adrenal blood flow, as well
as the Ang II-mediated stimulation of cell growth.
THE AT2 RECEPTOR

In contrast to the AT1receptor, much less is known about the structural and functional properties of the AT2receptor.
Activation of the AT2 receptors counteracts many of the effects of the AT1 receptors by having antiproliferative, anti-
inflammatory, vasodilatory, natriuretic, and antihypertensive effects.
Signaling through the AT2 receptor is mediated by G protein–dependent (Giα2 and Giα3) and G protein–independent
pathways.
 Consequences of AT2 receptor activation include activation of phosphotyrosine phosphatases that inhibit MAP kinases and
ERK 1/2; inhibition of Ca2+ channel functions; and enhancing NO, cyclic GMP, and bradykinin production.
The AT2 receptors can bind the AT1 receptors to antagonize and reduce their expression.
THE Mas RECEPTOR

Mas receptor axis is a negative regulator of the pressor, profibrotic, and antinatriuretic effects of the ACE/AngII/AT1
receptor axis of the RAS.
Activation of the Mas receptor by Ang(1–7) induces vasodilation, stimulates PI3K/Akt pathway that promotes NO
production,potentiates the vasodilatory effects of bradykinin, and inhibits AngII-induced activation of ERK1/2 and
NFκB; it has antiangiogenic, antiproliferative, and antithrombotic effects; and it is renoprotective and cardioprotective in
cardiac ischemia and heart failure.
The table below outlines the angiotensin II effect at different points. These will be
discussed in more detail.

Site Main Action

Arterioles Vasoconstriction
Kidney Stimulates Na+ reabsorption
Increased release of
Sympathetic nervous system
noradrenaline (NA)
Stimulates release of
Adrenal cortex
aldosterone
Increases thirst sensation and
Hypothalamus & posterior
stimulates anti-diuretic
pituitary gland
hormone (ADH) release
Effects of Angiotensin II
1)Cardiovascular Effects-

Angiotensin 2 acts on AT1 receptors found in the endothelium of arterioles throughout the circulation to
achieve vasoconstriction. This signalling occurs via a Gq protein, to activate phospholipase C and subsequently increase
intracellular calcium.

The net effect of this is an increase in total peripheral resistance and consequently, blood pressure.

2) Brain-

First, it binds to the hypothalamus, stimulating thirst and increased water intake.

Second, it stimulates the release of antidiuretic hormone (ADH) by the posterior pituitary. ADH, or vasopressin, acts to
increase water reabsorption in the kidney by inserting aquaporin channels at the collecting duct.

Finally, angiotensin II decreases the sensitivity of the baroreceptor reflex. This diminishes baroreceptor response to an
increase in blood pressure, which would be counterproductive to the goal of the RAAS.

The net effect of these interactions is an increase in total body sodium, total body water, and vascular tone.
Target Action Mechanism
Voltage-gated calcium
Renal artery
channels open and
and afferent Vasoconstriction
allow an influx of
arteriole
calcium ions 3)Renal Effects
Vasoconstriction
Efferent Activation of AT1
(greater than the
arteriole
afferent arteriole)
receptor Angiotensin II acts on the
kidneys to produce a variety of
Contraction, leading
Activation of Gq effects, including afferent and
Mesangial receptors and opening efferent arteriole constriction and
to a decreased
cells of voltage-gated
filtration area
calcium channels
increased Na+ reabsorption in
the proximal convoluted tubule.
Increased Na+/H+ These effects and their
antiporter activity and mechanisms are summarized in
adjustment of the the table.
Proximal
Increased Na+ Starling forces in
convoluted
reabsorption peritubular capillaries
tubule
to increase
paracellular
reabsorption
4)Sympathetic nervous system

*Angiotensin (ANG) II exerts several actions on the sympathetic nervous system. These
include a central action to increase sympathetic outflow, stimulatory effects on sympathetic
ganglia and the adrenal medulla, and actions at sympathetic nerve endings that serve to
facilitate sympathetic neurotransmission epinephrine.

*epinephrine exerts its effects by binding to α- and β-adrenergic receptors (or

adrenoceptors, so named for their reaction to the adrenal hormones) in
different tissues. In the blood vessels, it triggers vasoconstriction
(narrowing of blood vessels), which increases blood pressure.
5)Adrenal cortex

Finally, angiotensin II acts on the adrenal cortex to stimulate the release of aldosterone. Aldosterone is
a mineralocorticoid, a steroid hormone released from the zona glomerulosa of the adrenal cortex.

Aldosterone acts on the principal cells of the collecting ducts in the nephron. It increases the expression of apical
epithelial Na+ channels (ENaC) to reabsorb urinary sodium.  Furthermore, the activity of the basolateral Na+/K+/ATPase
is increased.

This causes the additional sodium reabsorbed through ENaC to be pumped into the blood by the sodium/potassium
pump. In exchange, potassium is moved from the blood into the principal cell of the nephron.

This potassium then exits the cell into the renal tubule to be excreted into the urine . As a result, increased levels of
aldosterone cause reduced levels of potassium in the blood.

Aldosterone may act on the central nervous system via the posterior pituitary gland to release vasopressin (ADH)
which serves to conserve water by direct actions on renal tubular resorption.
In contrast to angiotensin II, aldosterone is a steroid hormone. As a result, it enacts change by binding to nuclear
receptors and altering gene transcription.

Thus, the effects of aldosterone may take hours to days to begin, while the effects of angiotensin II are rapid.
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