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)
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
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
Castrop et al ; Physiology of Kidney ReninPhysiol Rev 90: 607–673, 2010
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
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
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
Diem T. DINH*, et aI:Angiotensin receptors : distribution,signalling and function:Clinical Science (2001) 100, ;481–492
ACTIONS OF AT1 RECEPTOR
1) Blood vessels –
vasoconstriction leading to
an increase in peripheral
vascular tone and systemic
blood pressure
Diem T. DINH*, et aI:Angiotensin receptors : distribution,signalling and function:Clinical Science (2001) 100, ;481–492
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
Diem T. DINH*, et aI:Angiotensin receptors : distribution,signalling and function:Clinical Science (2001) 100, ;481–492
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
Diem T. DINH*, et aI:Angiotensin receptors : distribution,signalling and function:Clinical Science (2001) 100, ;481–492
Diem T. DINH*, et aI:Angiotensin receptors : distribution,signalling and function:Clinical Science (2001) 100, ;481–492
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
Diem T. DINH*, et aI:Angiotensin receptors : distribution,signalling and function:Clinical Science (2001) 100, ;481–492
Mas RECEPTOR
Castrop et al ; Physiology of Kidney ReninPhysiol Rev 90: 607–673, 2010
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
MARTIN PAUL et alPhysiology of Local Renin-Angiotensin Systems :Physiology of Local Renin-Angiotensin Systems Physiol Rev 86: 747–803, 2006
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
MARTIN PAUL et alPhysiology of Local Renin-Angiotensin Systems :Physiology of Local Renin-Angiotensin Systems Physiol Rev 86: 747–803, 2006
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
MARTIN PAUL et alPhysiology of Local Renin-Angiotensin Systems :Physiology of Local Renin-Angiotensin Systems Physiol Rev 86: 747–803, 2006
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
MARTIN PAUL et alPhysiology of Local Renin-Angiotensin Systems :Physiology of Local Renin-Angiotensin Systems Physiol Rev 86: 747–803, 2006
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
PERRIN C. WHITE:Aldosterone: Direct Effects on and Productionby the HeartThe Journal of Clinical Endocrinology & Metabolism 88(6):2376–2383
FEEDBACK REGULATION OF ALDOSTERONE
HARMFUL EFFECT OF ALDOSTERONE
PERRIN C. WHITE:Aldosterone: Direct Effects on and Productionby the HeartThe Journal of Clinical Endocrinology & Metabolism 88(6):2376–2383
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
PERRIN C. WHITE:Aldosterone: Direct Effects on and Productionby the HeartThe Journal of Clinical Endocrinology & Metabolism 88(6):2376–2383
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
PERRIN C. WHITE:Aldosterone: Direct Effects on and Productionby the HeartThe Journal of Clinical Endocrinology & Metabolism 88(6):2376–2383
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
PERRIN C. WHITE:Aldosterone: Direct Effects on and Productionby the HeartThe Journal of Clinical Endocrinology & Metabolism 88(6):2376–2383
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
‘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
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
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
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