renin angiotensin aldosterone- updates

Dr Vijay AmaranthDr R. Barik

UPDATE ON UPDATE ON RAASRAAS

RAAS - INTRODUCTION

Coordinated hormonal cascade in the control of cardiovascular, renal, and adrenal function that governs fluid and electrolyte balance and arterial pressure.

Exciting new concepts: new peptides, new enzymes , novel receptors,

receptor-receptor interactions, and the local tissue RAS ,intracellular RAS.

The new expanded view covers both endocrine, paracrine ,autocrine and intracrine functions.

Discovery of SNPs in RAS - enhanced comprehension of the pathophysiology of complex disease .

RAS - complex and multilayered

Historical Perspective

In 1898, Tigerstedt and Bergmann : heat-labile substance in crude extracts of rabbit renal cortex termed “renin”.

heat-stable, short-lived pressor substance -termed “angiotonin” or “hypertensin” by competing investigators Page et al and Braun-Menendez et al who ultimately compromised on the term “angiotensin”.

The Classical Renin-Angiotensin System

Renin is produced and stored in granular JG cells in kidney.

Preprorenin >>> prorenin >>> renin . sequential cleavage of the N-terminal 20 and 46 amino

acids of preprorenin.

kidney also releases unprocessed prorenin via a constitutive pathway

prorenin accounts for about 70% to 90% of the immunoreactive renin.

Stretch receptors in the afferent arteriole, the sympathetic nerves ending in the

juxtaglomerular cells, and the composition of the tubular fluid reaching the macula densa

Rate-limiting step : cleaving the N-terminal portion of a large molecular weight globulin, angiotensinogen, to form the biologically inert decapeptide Ang- 1(1-10)

primary source is liver, also in kidney, brain, heart, vascular, adrenal gland, ovary, placenta, and adipose tissue.

Ang III and IV- in tissue with high levels of aminopeptidases A and N, such as brain and kidney tissue.

Ang III - in CNS , play an important role in tonic blood pressure maintenance and in hypertension.

Ang IV [(3-8)] is a hexapeptide . Some report that Ang IV is a vasorelaxative agent and this effect is contributed to activation of endothelial NOS

others: Cooperative effect of Ang IV on angiotensin II type 1 (AT1)-receptor signaling

The AT2 Receptor

gene - a single copy on the X chrmosome.

highly expressed in fetal mesenchymal tissues

clearly detectable in the adult kidney, heart, and blood vessels.

mediate vasodilation by stimulating the production of BK, NO, and cGMP

activates phospholipase A2 and prostaglandin generation.

In the heart, the AT2 receptor inhibits growth and remodeling, induces vasodilation, and is up-regulated in pathological states

Activation of the AT2 receptor mediates at least some of the beneficial effects of AT1 receptor blockade via a BK/NO/cGMP pathway.

This paradigm opens the door for potential synergistic therapeutic effects of AT2 receptor agonists in combination with AT1 receptor blockers.

The type 4 (AT4) receptors- mediate the release of plasminogen activator inhibitor 1 by Ang II and by the N-terminal truncated peptides (Ang III and Ang IV).

The AT4 receptor appears to be involved in memory acquisition and recall.

but the function of the type 3 (AT3) receptors is unknown.

Angiotensin-Converting Enzyme-2

In the year 2000, ACE 2 a zinc metalloprotease was discovered

gene mapped to the X chromosome in humans

ACE 2 may be a candidate gene in hypertension.

Pedominantely in endothiuelm of coronary and renal vasculature

ACE 2 probably counterbalances the enzymatic actions of ACE

Unlike ACE, this enzyme does not convert Ang I to Ang II and its activity is not affected by ACE inhibitors

Angiotensin (1–7) IN 1988 major biologically active peptide product of the RAS

ANG I by neutral-endopeptidase (NEP) 24.11 or prolyl-endopeptidase (PEP)

ANG II via PEP or prolyl-carboxypeptidase

NEP 24.11 plays a major role in both circulating and tissue ANG (1–7) formation

cleaved to biologically inactive fragments by aminopeptidases or ACE.

G protein-coupled receptor Mas originally described as a protooncogene

expressed in several organs including heart, kidney, blood vessels, and brain

intracellular signaling mechanisms are largely unknown may be coupled to a Gq/11 protein that activates phospholipase C (PLC)

In addition to BK potentiation at B2 receptor, promotes release of prostaglandins release of NO { PI3K/Akt pathway} vasodilation, inhibition of vascular cell growth, attenuation of ANG II-induced vasoconstriction

(pro)renin receptor

Transmembrane protein consisting of 350 amino acids ;cloned from mesangial cells

Prorenin/renin - not only aspartyl proteases but also hormones with specific cellular actions in their own right.

Relevant to the pathophysiology of hypertension, preeclampsia,and diabetes mellitus.

“receptor-associated prorenin system”(RAPS)

pathogenic mechanims dually activates the tissue renin-angiotensin system (RAS) and RAS-independent intracellular signaling via the receptor.

(pro)renin receptor

Activates mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase (ERK) pathway and increases several profibrotic mediators- (TGF-β), and (PAI-1), and the extracellular matrix components, fibronectin and collagen

receptor acts as a cofactor by increasing the efficiency of ANG I generation on the cell surface by receptor-bound prorenin and renin

Angiotensin Receptor Heterodimerization

AT1 receptor and the BK B2 receptor associate to form stable heterodimers ;

in vivo was shown to be potentially important in the mediation of increased ANG II responsiveness in preeclampsia

AT1 and AT2 receptors heterodimerize: no longer activate G proteins by AT1 .

Thus, it appears that the AT2 receptor can be a direct AT1

receptor-specific antagonist.

Local [tissue] RAS

New hypotheses and functional concept- based on the tissue-based synthesis of ANG II.

Convinced and strengthened by two major technical advances :the use of molecular biology and the availability of transgenic and knock-out models

local synthesis versus uptake from the circulation

Should not threaten the concept , since either mechanism could contribute to local ANG synthesis and actions.

Modern concepts of the tissue RAS, therefore, are function oriented.

Plasma RAS takes up the role of an acute “response unit,” whereas tissue-based ANG II formation is more linked to subacute and chronic modulation.

local RAS: should not be considered as an

opposing or alternative but rather as a complimentary or integrated functional concept of ANG formation and function.

Localization and Functional Aspects

RENAL RAS CARDIAC RAS Vasculature Nervous system Adipose tissue

CARDIAC RAS

Maintenance of an appropriate cellular milieu balancing stimuli inducing and inhibiting cell growth and proliferation as well as mediating adaptive responses to myocardial stress

Human heart chymase activates ANG I to ANG II but is not inhibited by ACEI

Normal fibroblasts express AT1 only but can recruit the AT2 receptor under certain pathological conditions

FUNCTION

INOTROPIC EFFECTS

HYPERTROPHIC EFFECTS - activation of MAP kinase and JAK/STAT pathways;

MECHANICAL STRETCH

REMODELING: mediated through growth factor pathways induced by AT1 .

osteopontin - vascular smooth muscle cell remodeling , cardiac fibroblast behavior

AC-SDKP: a hematopoetic stem cell regulator, plasma marker for efficient ACE inhibition

antiproliferative effects

APOPTOSIS - cardiac remodeling for example, after myocardial infarction , hypertensive cardiomyopathy , and diabetic cardiomyopathy

RAAS and cardiac arrhythmias Electrical remodeling

cardiac hypertrophy, fibrosis, and heterogeneity of the cardiac tissue

RAAS, oxidative stress, and arrhythmias

RAAS and ion channels

RAAS and cardiac arrhythmias

INTRACELLULAR RAS INTRACRINE HORMONAL SYSTEM : Although

controversial none of the components would have to be

secreted into the extracellular space to engender a biological action.

renin and prorenin might have the capability to

act intracellularly, as well as ANG II and other ANG peptides.

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25

50

75

100

0

10

20

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Placebo 4 h 24 h 1 2 3 4 5 6

Time, months

Plasma Angiotensin-Converting Enzyme,

nmol/mL/min

Plasma Angiotensin II,

pg/mL

Biollaz J et al. J Cardiovasc Pharmacol. 1982;4:966-972.

*

Angiotensin II Returns to Baseline LevelsAngiotensin II Returns to Baseline LevelsAngiotensin II Returns to Baseline LevelsAngiotensin II Returns to Baseline Levels

** * * * * * *

ACE Escape With Long-TermACE Escape With Long-TermACE Inhibitor TreatmentACE Inhibitor Treatment

*P<.001 vs placebo.

ACEI, angiotensin-converting enzyme inhibitor; Ang, angiotensin.

HBPHBP VASCULARVASCULAR MIMI HFHF

PRE-DIABETESPRE-DIABETES DIABETES DIABETES OPTHALOPTHAL

DIABETES RENALDIABETES RENAL

(DIRECT)(DIRECT)

LIFE LIFE

SCOPESCOPE

LIFE LIFE

SCOPESCOPEOPTIMAALOPTIMAALOPTIMAALOPTIMAAL

CHARMCHARMCHARMCHARM VALUEVALUE VALUEVALUE

VALIANTVALIANTVALIANTVALIANT

(NAVIGATOR)(NAVIGATOR) (NAVIGATOR)(NAVIGATOR)

(ONTARGET)(ONTARGET)(TRANSCEND)(TRANSCEND)

JIKEIJIKEI

(ONTARGET)(ONTARGET)(TRANSCEND)(TRANSCEND)

JIKEIJIKEI

ELITE IIELITE II

Val-HeftVal-Heft

ELITE IIELITE II

Val-HeftVal-Heft

RENAALRENAAL

IDNTIDNT

RENAALRENAAL

IDNTIDNT

ATAT11-Receptor Blocker (ARB)-Receptor Blocker (ARB)

ATRIAL FIBATRIAL FIB (ACTIVE)(ACTIVE)ATRIAL FIBATRIAL FIB (ACTIVE)(ACTIVE)

(I-PRESERVE)(I-PRESERVE)

Clinical Outcome StudiesClinical Outcome Studies Clinical Outcome StudiesClinical Outcome Studies

Aldosterone antagonism

Aldosterone antagonism

ACEI/ARB combinations

different cardiovascular outcomes [ CHARM-Added, Val-HeFT, VALIANT vs RESOLVD Pilot Study Investigators ] may relate to different patient populations, previous or concurrent successful treatment with other drugs, or study design

PRA is related to adverse clinical outcomes further raises the possibility that DRIs may be useful.

Pepstatin - The first synthetic renin inhibitor but required parenteral administration.

Oral agents : enalkiren, remikiren, and zankiren had limited clinical use

poor bioavailability (<2%) short halflives weak antihypertensive activity .

ALISKIRENALISKIREN

Octanamide, new class of nonpeptide, low molecular weight, orally renin inhibitors

At a dose of 300 mg decreases PRA by 50%–80

The plasma half-life of 23–70 hours

Wood et al. BBRC 2003.

Aliskiren Binding to Renin

Renin

Aliskiren bound toActive site

Metabolism by Cytochrome P450 (CYP3A4)

No change of dose in hepatic and renal insufficiency

Adverse events : diarrhea, headache, nasopharyngitis, dizziness, fatigue, back pain, gastrointestinal disorders, rash, and renal stone cough and angioedema

PRORENIN RECEPTOR

handling region peptide (HRP) inhibiting the binding of prorenin to (P)RR

non-peptide (P)RR antagonist (i.e. a renin/prorenin receptor blocker, RERB)

AT2R agonists

Recently discovered non-peptide agonist, compound 21

Inhibits MAPKs, activates NO/cGMP and phospholipase A2 pathways- mediating anti-proliferation, vasodilation, and anti-inflammation.

Mas may also partially antagonize the AT1R effects- some therapeutic potential In rat studies

Vasopeptidase inhibitors

OCTAVE and OVERTURE : ACE/NEP inhibition omapatrilat but higher incidence of angioedema .

Dual AT1R/NEP antagonism (angiotensin receptor and neprilysin inhibitors, ARNI) could show a more favourable tolerance profile

Gene-based therapies

aOverexpression of ACE2 and AT2R delivered in viral vectors reduced cardiac remodelling.

Exciting, but more safe and reliable methods of nucleic acid transfer re required.

Vaccine-based strategies

Two antihypertensive vaccines were developed: PMD3117 against Ang I and Cyt006 against Ang II

Seems feasible and preventive employment against CV diseases.

Molecular therapy

Ang-(1-7) inhibited mitogen-stimulated VSMC growth and reduced neointimal formation after vascular injury.

Increased the vascular content of cAMP in VSMCs

Inhibits angiogenesis - role in treatment of various tumors