renin angitensin aldosterone system- updates

1. UPDATE ON
RAAS
Dr Vijay Amaranth
Dr R. Barik

2. 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.

3.  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

4. 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”.

5. 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.

6. 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

8.  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.

16.  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

20. 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

21.  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

22.  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.

23.  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.

26. 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.

27.  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

28. 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.

30.  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)

32.  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

35. (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.

36. “receptor-associated prorenin system”
(RAPS)
 pathogenic mechanims dually activates the
tissue renin-angiotensin system (RAS) and
RAS-independent intracellular signaling via the
receptor.

38. (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

39. 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.

40. 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

42. 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.

43.  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.

44. Localization and Functional Aspects
 RENAL RAS
 CARDIAC RAS
 Vasculature
 Nervous system
 Adipose tissue

46. 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

47.  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

48. FUNCTION
 INOTROPIC EFFECTS
 HYPERTROPHIC EFFECTS - activation of MAP
kinase and JAK/STAT pathways;
 MECHANICAL STRETCH

50.  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

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

52. RAAS and cardiac arrhythmias
Electrical remodeling
 cardiac hypertrophy, fibrosis, and
heterogeneity of the cardiac tissue
 RAAS, oxidative stress, and arrhythmias
 RAAS and ion channels

53. RAAS and cardiac arrhythmias

58. 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.

61. ACE Escape With Long-Term
ACE Inhibitor Treatment
Angiotensin II Returns to Baseline Levels
100
Plasma
Angiotensin- 75
Converting
50
Enzyme,
nmol/mL/min 25 * * * * *
* * *
0
30
Plasma 20
Angiotensin II,
pg/mL
10 *
0
Placebo 4 h 24 h 1 2 3 4 5 6
Time, months
*P<.001 vs placebo.
ACEI, angiotensin-converting enzyme inhibitor; Ang, angiotensin.
Biollaz J et al. J Cardiovasc Pharmacol. 1982;4:966-972.

63. AT1-Receptor Blocker (ARB)
Clinical Outcome Studies
HBP VASCULAR MI HF
LIFE (ONTARGET) OPTIMAAL ELITE II
SCOPE (TRANSCEND) VALIANT Val-Heft
VALUE JIKEI
CHARM
(I-PRESERVE)
PRE-DIABETES DIABETES DIABETES RENAL
(NAVIGATOR) OPTHAL
(DIRECT) RENAAL
ATRIAL FIB IDNT
(ACTIVE)

64. Aldosterone antagonism

65. Aldosterone antagonism

66. 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.

69.  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 .

70. ALISKIREN
 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

71. Aliskiren Binding to Renin
Renin
Aliskiren bound to
Active site
Wood et al. BBRC 2003.

72.  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

76. 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)

77. 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

78. 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

79. 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.

80. 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.

81. 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