physiology & pathophysiology of raas

CMC CALICUT

PHYSIOLOGY &

PATHOPHYSIOLOGY OFRAAS

DR.SANDEEP R

SR , DEPT. OF CARDIOLOGY

1) HISTORY

2) ANGIOTENSINOGEN

3) RENIN

4) ACE

5)ANGIOTENSINS

6)ANGIOTENSIN RECEPTORS

7)LOCAL RAAS

8)CARDIAC RAAS

9)ALDOSTERONE

9)PATHOPHYSIOLOGY OF RAAS

HISTORY

Robert Tigerstedt and Per Bergman from Sweden in their

seminal 1898 report, Niere und Kreislauf, described the

prolonged vasopressor effects of crude rabbit kidney

extracts.

Tigerstedt named the unidentified active substance “renin”

on the basis of its organ of origin.

Steven A. Atlas, MDJThe Renin-Angiotensin Aldosterone System: Pathophysiological Role and Pharmacologic Inhibition J Manag Care Pharm. 2007;13(8)(suppl S-b):S9-S20

Goldblatt and colleagues, published in 1934, that showed that renal ischemia induced

by clamping of the renal artery could induce hypertension.

Ischemic kidney also released a heat-stable, short-lived pressor substance, in

addition to renin.

This finding eventually led to the recognition that renin’s pressor activity was indirect

and resulted from its proteolytic action on a plasma substrate (eventually termed

“angiotensinogen”) to liberate a direct-acting pressor peptide.

This peptide was initially termed “angiotonin” or “hypertensin” by Page &

colleagues(US)

Ultimately named “angiotensin” by Braun-Menendez & colleagues(ARGENTINA)


In the early 1950s, during attempts at purification, Skeggs &

colleagues discovered that this peptide existed in 2 forms, eventually

termed Ang I and II.

In later work, they demonstrated that Ang I was cleaved by a

contaminating plasma enzyme,termed “angiotensin-converting

enzyme,” to generate the active pressor peptide Ang II.

Laragh, Genest, Davis, Ganong, and their colleagues, culminated in

the discovery that Ang II also stimulated the release of the adrenal

cortical hormone aldosteroneSteven A. Atlas, MDJThe Renin-Angiotensin Aldosterone System: Pathophysiological Role and Pharmacologic Inhibition

J Manag Care Pharm. 2007;13(8)(suppl S-b):S9-S20

ANGIOTENSINOGEN The primary source of systemic circulating angiotensinogen is the liver

particularly the pericentral zone of the hepatic lobules.

It is coded by a single gene, composed of five exons and four introns, that

spans approximately13 kb of genomic sequence on chromosome 1 (1q42-q43).

Also detected in many other tissues, including kidney, brain, heart, vascular,

adrenal gland, ovary, placenta, and adipose tissue

Rise in response to glucocorticoids, estrogens and other sex steroids, thyroid

hormone, inflammatory cytokines (e.g., interleukin-1 and tumor necrosis factor),

and Ang II.Ron D, Brasier AR, Habener JF. Angiotensinogen gene-inducible enhancer-binding protein 1, a member of a new family of large nuclear

proteins that recognize nuclear factor kappa B-binding sites through a zinc finger motif. Mol Cell Biol. 1991;11:2887-2895.

RENIN Glycoprotein (Mw 37,326)

Renin gene located in CHR.1

Synthesized from preprorenin

Mature active renin is an aspartyl protease secreted by juxtaglomerular cells

Richard E. Gilbert, David S. Game, and Andrew Advani:BRENNERS TEXTBOOK OF NEPHROLOGY;2010;12;384-385

JUXTAGLOMERULAR APPARATUS

The Juxtaglomerular Apparatus consists of:

(1) The juxtaglomerular cells

(2) The macula densa

(3) The lacis cells or agranular cells

RENIN -SYNTHESIS

PREPRORENIN( 406 aminoacid)

PRORENIN (383 aminoacid)

RENIN (340 aminoacid)

Renin is also synthesized In brain, adrenal gland, ovary, visceral adipose tissue,

heart and vasculature

Half life of renin is 80 mt

Only action of renin is conversion of angiotensinogen to angiotensin I

REGULATION OF RENIN

Active renin secretion is regulated principally by 4 interdependent

factors:

(1) A renal baroreceptor mechanism in the afferent arteriole that

senses changes in renal perfusion pressure,

(2) Changes in delivery of NaCl to the macula densa cells of the

distal tubule

(3) Sympathetic nerve stimulation via beta-1 adrenergic receptors

(4) Negative feedback by a direct action of Ang II on the JG cells.

HAYO CASTROP, KLAUS HO ¨ CHERL, ARMIN KURTZ, FRANK SCHWEDA, VLADIMIR TODOROV,AND CHARLOTTE WAGNER; Physiology of Kidney Renin: Physiol Rev 90: 607–673, 2010;

REGULATION OF RENIN SECRETION

1.INTRARENAL MECHANISM

Renal baroreceptor mechanism

Renin secretion increases as the blood pressure falls below 90mmhg

The precise mechanism , how the pressure signal is transduced into renin release is still unknown, although

postulated mediators include stretch-activated calcium channels, endothelins, and prostaglandins

JG cells are strongly electrically coupled to the neighboring cells of the afferent arteriole .

Interestingly, their resting membrane potential changes in situ from -60 to -80 mV in nonpressurized

arterioles to approximately -40 mV in pressurized arterioles

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

HAYO CASTROP ET AL; Physiology of Kidney Renin: Physiol Rev 90: 607–673, 2010;

2.NEURAL CONTROL

The JGA is endowed with a rich network of noradrenergic nerve endings and

their β1 receptors

Stimulation of the renal sympathetic nerve activity leads to renin secretion that

is independent of changes in renal blood flow, glomerular filtration rate (GFR),

or Na+ resorption

Moreover, this effect can be blocked surgically by denervation and

pharmacologically by the administration of β blockers

3.TUBULAR CONTROL Chronic diminution in luminal NaCl delivery to the macula densa is a

potent stimulus for renin secretion

This mechanism is thought to account for the chronically high plasma

renin activity (PRA) in subjects who adhere to a low-salt diet

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.

HAYO CASTROP ET AL; Physiology of Kidney Renin: Physiol Rev 90: 607–673, 2010;

DISTAL TUBULAR SODIUM ↑

INCREASED UPTAKE INTO MACULA DENSATHROUGH NA/K+/2CL CHANNEL

MACULA DENSA Na+ & FLUID CONTENT↑

SWELLING OF MACULA DENSA & STRETCH

STRETCH CAUSES ADENOSINE RELEASE

A2 CAUSES ↓RENIN SECRN

NO SYNTHETASE ↓DECREASES RENIN

DISTAL TUBULAR SODIUM ↓

Na+ UPTAKE IN MACULA DENSA ↓

ACTIVN OF NOSYNTHETASE

PG SYNTHESIS

STIMULATE RENIN RELEASE

The detection done by Na-K-

2Cl cotransporter in the apical

membrane of tubular cells

Three mediators -

prostanoids, NO, and

adenosine/ATP

Castrop et al ; Physiology of Kidney ReninPhysiol Rev 90: 607–673, 2010

REGULATION OF RENIN

FACTORS THAT INCREASE RENIN RELEASE

1)Catecholamines 2)Bradykinin 3)Dopamine 4)NO 5)Prostaglandins


FACTORS THAT DECREASE RENIN RELEASE

1) ANG II2) VASOPRESSIN3) A N P4) IL65) TNF - ALPHA6) ADENOSINE

MOLECULAR MECHANISM OF RENIN RELEASE

C-amp mediated - sympathetic, prostaglandin E2 & I2,dopamine

Calcium paradox - increase in intracellular Ca2+ decrease renin release-endothelin,vasopressin,Ang II

C-GMP

Low consc. stimulates &

High consc. Inhibits - NO

Castrop et al ; Physiology of Kidney Renin Physiol Rev 90: 607–673, 2010

PRORENIN Traditionally, prorenin was considered the inactive precursor of renin

The Current studies implicate prorenin and renin as direct cardiac and renal toxins

Prorenin is inactive because a 43–amino acid hinge is closed and prevents it from binding to angiotensInogen

Prorenin & renin levels increased by ACE inhibitor , ARB , DRI

Richard E. Gilbert, David S. Game, and Andrew Advani:BRENNERS TEXTBOOK OF NEPHROLOGY;2010;12;384-385

PRORENIN RECEPTOR

The kidneys convert inactive prorenin to active renin by enzymatic cleavage of this inhibitory hinge region

When circulating prorenin binds to a newly discovered (pro)renin receptor in the heart and kidneys, the hinge is opened (but not cleaved), and this nonenzymatic process fully activates prorenin

Direct Renin Inhibition: Focus on Aliskiren James L. Pool, MD JMCP October 2007 Vol. 13, No. 8, S-b

RENIN/PRORENIN RECEPTOR

The existence of high-affinity cell surface receptors that bind both renin

and prorenin in several tissues, including heart, brain placenta, and kidney but its significance still unknown

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

Activation of the (pro)renin receptor increases TGF-β production, leading to collagen deposition and fibrosis

Direct Renin Inhibition: Focus on Aliskiren James L. Pool, MD JMCP October 2007 Vol. 13, No. 8, S-b

ACE ACE is responsible for the cleavage of

Ang I to form the octapeptide Ang II

ACE cleaves bradykinin into inactive fragments

Human ACE in encoded by a single gene located on chromosome 17

The majority ( 90%) of ACE activity in the ∼body is found in tissues; the remaining 10% of ACE activity is found in a soluble (non–membrane bound) form in the interstitium of the heart and vessel wall

It is seen pulmonary vascular endothelium, endothelium of vasculature ,cell membrane of heart , kidneys & brain

ACE 2 ACE2 represents a zinc metalloprotease with carboxypeptidase activity that

shares 42% identity with the catalytic site of somatic ACE and can be shed from cells

ACE2 can convert ANGII to ANG 1-7 & ANG I to ANG 1-9

Preferable physiological substrate for ACE2 seems to be ANG II

The expression of ACE2 is (in comparison with ACE) relatively restricted to cardiac blood vessels and tubular epithelia of the kidneys

ACE 2 cannot hydrolyze bradykinin and is not inhibited by ACE inhibitors

Actual function and significance is still unknown

ACE2 is the functional receptor for coronavirus associated with the acute respiratory syndrome, i.e., SARS

ANGIOTENSIN SYNTHESIS

ANGIOTENSIN RECEPTORS

ANGIOTENSIN RECEPTORS

1)AT1

2)AT2

3)AT3

4)AT4

5)Mas receptor

AT1 RECEPTOR

AT1 - G protein coupled receptor

Chromosome 3

AT1A receptors are found predominantly in kidney, lung, liver and

vascular smooth muscle

AT1B receptors are expressed mainly in the adrenal and anterior

pituitary glands.

Diem T. DINH*, et aI:Angiotensin receptors : distribution,signalling and function:Clinical Science (2001) 100, ;481–492

AT1 receptors are primarily found in the

1)Brain-hypothalamus,NTS and ventrolateral medulla in the

hindbrain,ant.pituitary

2)Adrenals- the zona glomerulosa of the adrenal cortex and

chromaffin cells of the adrenal medulla

3) Heart - in the conducting system , nerves of myocardium

4)Vasculature-the aorta, pulmonary and mesenteric arteries, are

present in high levels on smooth muscle cells and low levels in

the adventitia

5) Kidney – glomerular mesangial cells and renal interstitial cellsDiem T. DINH*, et aI:Angiotensin receptors : distribution,signalling and function:Clinical Science (2001) 100, ;481–492

AT1 RECEPTOR

The predominant angiotensin receptor in the vasculature is the AT1 receptor

Although both the AT1 and AT2 receptor subtypes are present in human myocardium

Ratio of AT1 to AT2 receptors decreases in heart failure


ACTIONS OF AT1 RECEPTOR

1) Blood vessels –

vasoconstriction leading to

an increase in peripheral

vascular tone and systemic

blood pressure


2)Heart

Positive ionotropic and chronotropic effects of Ang II on cardiomyocyte

1)INCREASED SYMPATHETIC ACTIVITY

2)INCREASED CA2+ INFLUX

Ang II is also known to

mediate cell growth and proliferation in cardiac myocytes and fibroblasts, as well as in vascular smooth muscle cells via TGF,PDGF etc Diem T. DINH*, et aI:Angiotensin receptors : distribution,signalling and function:Clinical Science (2001) 100, ;481–492

3) Adrenal -Ang II stimulates the release of catecholamines from the

adrenal medulla and aldosterone from the adrenal cortex

Trophic factor for zona glomerusa

4) Brain- thirst , salt appetite, central control of blood pressure,

stimulation of pituitary hormone release and has effects on learning

and memory


5)RENAL

It increases salt reabsorbtion – direct & indirect

Direct effect

Renal arterioles constriction

Peritubular capillary pressure

Fluid reabsorptionFrom tubules

Proximal Tubular Epithelial cells

Sodium reabsorbtion

INDIRECT ACTION OF ANG II IN KIDNEY

ANGIOTENSIN II

SYMPATHETIC ACTIVATION

MESANGIAL CONTRN

GFR

ADRENAL CORTEX STIMLN.

ALDOSTERONE SECRETION

SALT & WATER RETENTION

AT2 RECEPTOR The AT2 receptor is also a seven transmembrane domain receptor, encoded

by a 363-amino-acid protein( MW 41 kDa)

Shares only 34% sequence identity with the AT 1 receptor

The AT2 receptor -highly expressed in foetus but rapidly declines at birth

AT2 receptors are present in brain, heart, adrenal medulla, kidney and

reproductive tissues


AT2 RECEPOR & ITS ACTIONS Brain – cerebellum

Heart - fibroblasts in interstitial regions

Adrenal- adrenal medulla

Kidney- the AT2 receptor is localized to glomeruli, tubules and renal blood vessel

ACTIONS

Vasodilation

Antiproliferative

Apoptosis

Thirst Diem T. DINH*, et aI:Angiotensin receptors : distribution,signalling and function:Clinical Science (2001) 100, ;481–492

AT3 & AT4

Type 3 (AT3) receptors – Function unknown

The type 4 (AT4) receptors - mainly mapped in brain & kidney

Thought to mediate the release of plasminogen activator inhibitor 1 by

Ang II and by the N-terminal truncated peptides (Ang III and Ang IV)

Suggested a role in mediating cerebral and renal blood flow, memory

retention and neuronal development


Mas RECEPTOR


Mas receptor - Acted upon

by ANG1-7

Causes

1) Vasodilatation

2) Natriuresis

3) Antiproliferation

4) Cardiac protection

LOCAL RAS

Angiotensin II is found to be synthesized in the various tissues through ACE & non ACE pathways

Independent Ang II - heart, peripheral blood vessels, kidney, brain, adrenal glands, pituitary, adipose tissue, testes, ovaries, and skin.

COMPONENTS : 1) Renin and Prorenin receptor 2) Serine proteases, including several kallikrein-like enzymes (tonins),

cathepsin G, and chymase are thought to contribute to Ang II 3) Non-ACE pathways- chymase is the dominant Ang II-generating

pathway in the human heart, coronary arteries, and atherosclerotic aorta in vitro

4)ACE 2 ,Mas receptor,AT2 , AT4

The Renin-Angiotensin Aldosterone System: Pathophysiological Role and Pharmacologic Inhibition Vol. 13, No. 8, S-b October 2007 JMCP

LOCAL RAS

CARDIAC RAAS

MARTIN PAUL et alPhysiology of Local Renin-Angiotensin Systems :Physiology of Local Renin-Angiotensin Systems Physiol Rev 86: 747–803, 2006

1

1)RENIN

2)RENIN RECEPTOR

3)ANGIOTENSINOGEN

4)CHYMASE

5)ACE 2

6)AT1& AT2 RECEPTOR

CARDIAC RAS

Predominant physiological role of the cardiac RAS appears to be the

maintenance of an appropriate cellular milieu balancing stimuli inducing

and inhibiting cell growth and proliferation as well as mediating adaptive

responses to myocardial stress, for example, after myocyte stretch

EFFECTS OF CARDIAC RAAS

1)Ionotropic Effect

Positive ionotropic and chronotropic effects of Ang II on cardiomyocyte

1)INCREASED SYMPATHETIC ACTIVITY

2)INCREASED CA2+ INFLUX

2)Hypertrophy

Ang II is also known to mediate cell growth and proliferation in cardiac myocytes and fibroblasts, as well as in vascular smooth muscle cells via TGF,PDGF


3)Mechanical stretch- stretch can cause release of ANG II

causing hypertrophy and remodelling

4)Cardiac remodelling – stretch causing fibroblast activation

through AT1 receptor.

Increased activity of the system has also been linked to

changes in the electrical physiology that lead to arrhythmias

both in the ventricle and atria

5) Apoptosis – remodelling during M.I , DCMPY etc


VASCULATURE RAS 1) Vasoconstriction

2) Oxygen free radicals causing endothelial dysfunction

The production of ROS by NAD(P)H oxidase in reponse to ANG II

stimulation in endothelial and vascular smooth muscle cells

activates signal pathways such as MAP kinases, tyrosine kinases

may lead to inflammation , artherosclerosis, hypertrophy

3)Angiogenesis


GENDER DIFFERENCES IN CARDIAC RAS 1)AT1 receptor downregulated by estrogen

2)Increased pdn. Of ANG 1-7 –vasodilator peptide

3)Ventricular ACE activity is more in males

4)Estrogen decreases renin production

5)Angiotensinogen production is stimulated by testosterone


ALDOSTERONE

Mineralocorticoid It is synthesized in the zona

glomerulosa of adrenal cortex

It is stimulated by 1)ACTH 2)ANG II 3)HYPERKALEMIA 4) HYPONATREMIA

Cholesterol

Pregnenolone

Progesterone

Deoxycorticosterone

Corticosterone

18-Hydroxycorticosterone

Aldosterone

ACTH/AII

ALDOSTERONE SYNTHASE

ALDOSTERONE SYNTHASE/AII

ALDOSTERONE SYNTHASE

MINERALOCORTICOID RECEPTOR

Mineralocorticoid receptor can bind

cortisol, aldosterone &

deoxycortisone

The affinity of cortisol to MR

receptor is ten times its affinity to

GR receptor

This is prevented by the presence

of 11 beta dehydrogenase 2 which

converts cortisol to

cortisone( inactive )

This is the basis of syndrome of

apparent mineralocorticoid excess

(AME)PERRIN C. WHITE:Aldosterone: Direct Effects on and Productionby the HeartThe Journal of Clinical Endocrinology & Metabolism 88(6):2376–2383

ALDOSTERONE ACTION

PERRIN C. WHITE:Aldosterone: Direct Effects on and Productionby the HeartThe Journal of Clinical Endocrinology & Metabolism 88(6):2376–2383

Acts on P cells inCollecting duct

Causes increased activity of Enac

Causes Na/K exchangers

REGULATION OF ALDOSTERONE


FEEDBACK REGULATION OF ALDOSTERONE

HARMFUL EFFECT OF ALDOSTERONE


EFFECTS OF ALDOSTERONE ON HEART

1)Cardiac fibrosis - by acting through mineralocorticoid receptor in

cardiac fibroblast causing activation of MAP kinase

2)Perivascular inflammation- endothelial dysfunction permitting

adhesion of inflammatory cells to the vascular wall and egress into the

perivascular space

Indeed, aldosterone causes endothelial dysfunction in humans in vivo

possibly by decreasing NO through superoxide generation


3)Cardiac hypertrophy Increased intracellular calcium might ultimately cause cardiac

hypertrophy by increasing the expression of calcineurin, a

calcium/calmodulin-dependent protein phosphatase

Increase ACE activity causing ANGII causing hypertrophy


4) Electrophysiologic abnormalities

in heart

Aldosterone causes increase in

intracellular calcium/increase in

sodium flux which may cause

arrythmia

All enzymes required for synthesis

of deoxycorticosterone and (in the

atria) corticosterone are expressed

in the normal human heart


‘ONE KIDNEY’ GOLDBLATT HYPERTENSION

Initial rise in hypertension is due to renin secretion leading to angiotensin II

Secretion of renin peaks in one day but gradually decreases over 5-7 days as the renal perfusion improves

Second rise is due to increase in aldosterone

“TWO KIDNEY” GOLDBLATT HYPERTENSION

If there are two kidneys and

one is clamped

Then the ischaemic kidney

releases the renin

This renin causes fluid and

salt retention in both the

normal and abnormal kidney

This leads to hypertension

RAS IN HEART FAILURE In contrast to the sympathetic nervous system, the

components of the RAS are activated comparatively later in HF

The presumptive mechanisms for RAS activation in HF

include 1) Renal hypoperfusion 2)Decreased filtered sodium reaching the macula densa in

the distal tubule 3)Increased sympathetic stimulation of the kidney, leading to

increased renin release from the juxtaglomerular apparatus

BIBLIOGRAPHY 1)Steven A. Atlas, MDJThe Renin-Angiotensin Aldosterone System: Pathophysiological Role and

Pharmacologic Inhibition J Manag Care Pharm. 2007;13(8)(suppl S-b):S9-S20 2) PERRIN C. WHITE:Aldosterone: Direct Effects on and Productionby the HeartThe Journal of

Clinical Endocrinology & Metabolism 88(6):2376–2383 3) MARTIN PAUL et alPhysiology of Local Renin-Angiotensin Systems :Physiology of Local Renin-

Angiotensin Systems Physiol Rev 86: 747–803, 2006 4) Diem T. DINH*, et aI:Angiotensin receptors : distribution,signalling and function:Clinical Science

(2001) 100, ;481–492 5) Direct Renin Inhibition: Focus on Aliskiren James L. Pool, MD JMCP October 2007 Vol. 13,

No. 8, S-b 6) Richard E. Gilbert, David S. Game, and Andrew Advani:BRENNERS TEXTBOOK OF

NEPHROLOGY;2010;12;384-385 7) HAYO CASTROP, KLAUS HO ¨ CHERL, ARMIN KURTZ, FRANK SCHWEDA, VLADIMIR

TODOROV,AND CHARLOTTE WAGNER; Physiology of Kidney Renin: Physiol Rev 90: 607–673, 2010;

8) Ron D, Brasier AR, Habener JF. Angiotensinogen gene-inducible enhancer-binding protein 1, a member of a new family of large nuclear proteins that recognize nuclear factor kappa B-binding sites through a zinc finger motif. Mol Cell Biol. 1991;11:2887-2895.

9)GUYTON &HALL MEDICAL PHYSIOLOGY 12TH EDITION

physiology & pathophysiology of raas

Documents

active renin

renin gene

termed angiotensin

active pressor peptide

suppl sb

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pathophysiological role

termed angiotonin