Rensin Aldosterone System

RAAS (Renin Angiotensin Aldosterone System) plays a role in the homeostatic process such as blood pressure and fluid volume control1. Renin is secreted in the blood from cells that are lining the glomeruli of the kidneys. The renin-secreting cells are sensitive to changes in blood flow and blood pressure. Angiotensinogen, a glycosylated protein that is primarily synthesized and secreted by the liver as well as other tissues is the sole precursor for angiotensin peptide. Renin catalyzes the conversion of a plasma protein called angiotensinogen into a decapeptide (consisting of 10 amino acids) called angiotensin I. An enzyme in the serum called angiotensin-converting enzyme (ACE) then converts angiotensin I into an octapeptide (consisting of

eight amino acids) called angiotensin II. Angiotensin II acts via receptors in the adrenal glands to stimulate the secretion of aldosterone, which stimulates salt and water reabsorption by the kidneys, and the constriction of small arteries (arterioles), which causes an increase in blood pressure. The renin angiotensin system (RAS), a potent regulator of blood pressure, plays a major role in the pathogenesis of cardiovascular diseases. Emerging evidence suggests that angiotensin (Ang) II is not the only active peptide of the RAS. Other members of the system; Ang III [Ang-(2–8)], Ang IV [Ang-(3–8)], and Ang-(1–7) may also mediate the actions of the RAS. The vascular and baroreflex actions of Ang-(1–7) counteract those of Ang II. Two receptor subtypes have been identified for the Renin, AT1 and AT2. AT1 receptors mediates most of effects of Angiotensin II. This receptor consist of 359 amino acids and it is 40 kDA molecular weight protein. AT1 receptor is a member of G-Protein coupled receptors, which are having seven trans membrane domains. Intrestingly, AT1 receptor couples with Gq subunit of GPCR complex and results in the activation of downstream intracellular signaling cascade that activates PLC (Phospholipase C), Phospholiapse A2 and Phsopholipase D.

PLC activation is involved in the enhanced inositol triphosphate (IP3) and diacylglycerol. IP3 promotes the release of calcium from the intracellular sources and DAG (diacylglycerol) activates Protein Kinase C (PKC). Angiotensin II exhibits its function of vasoconstriction via AT1 receptor. ANG II also exerts functions like renal tubular salt absorption, stimulation of aldosterone release and also elicit effects like thirst and vasopressin secretion. Under certain Pathological conditions scientist have found that ANG II generated via renin system is involved in the promotion of vascular remodeling, cardiac hypertrophy remodeling and ECM deposition. Three different mechanisms are involved in the AT1 receptor regulation, transcription and modulation of activity of this receptor. AT2 receptor consist of 363 amino acids and molecular mass of 41 kDA. It is also a seven trans membrane receptor like AT1 receptor. If we evolutionary relationship is considered AT1 and AT2 are 34%

homologues. AT2 receptors function is still not widely understood but it is observed in the preliminary experiment that AT2 receptor signaling antagonize the effects of Angiotensin II on AT1 receptors. In these experiments it was found that AT2 receptors undergoes hetero dimerization with AT1 receptors which eventually attenuates the AT1 mediated effects of Angiotensin II. AT2 receptor knockdown leads to increase in the blood pressure in case of experimental mice, that means AT2 receptor causes vasodilation.
Renin/Pro-renin Receptor: - Function of Renin is not limited to angiotensinogen cleavage but pro-renin receptor is involved in the binding of the renin receptor to mesangial cells. Renin/ Pro-renin receptor is transmembrane receptor with single subunit and molecular mass of 45-kDa. This renin/pro-renin receptor can bind to both renin and pro-renin and it has 350 amino acids. It does not share any homology with any known receptors. When renin binds with renin/pro-renin receptor the enzyme catalytic activity is increased in the order of 5 fold. When pro-renin binds with this receptor its enzymatic activity is also increased but the mechanism is still poorly understood. But it is suggested that pro-renin uses its handle region to bind with renin/pro-renin receptor and this binding exposes the active site of the enzyme for the reaction. Binding of pro-renin and renin to renin/pro-renin receptor increases the renin activity and also intracellular signaling of cells expressing these two receptors. In the study involving SHR rats it was found that therapeutic benefit of renin/pro-renin is substantial and inhibition of this receptors via specific renin/pro-renin increases cardiac fibrosis. Study in the SHR rats helped to identify a novel receptor that binds both renin and pro-renin and has equal affinity for both renin and pro-renin. When renin/Pro-renin binds with the receptor dual effects are observed, first is the increase in the enzyme activity of renin and pro-renin and local renin/pro-renin trapping effect.
ANG-(1–7)/ACE2/Mas Axis
Recently, it has been found that small peptides of RAAS which includes ANG II, ANG (1-7), and ANG IV, also have biological activity but plasma content of these small peptides is much lower than ANG II.

However, ANG (1-7) is the exception to this observation. ACE homolog ACE 2 is required for the generation of ANG (1-7) and G-Protein coupled Mas receptor. ANG (1-7) exhibits its effects through Mas receptor. This axis is having counter-regulatory effect to classical RAAS pathway. ANG (1-7) is a heptapeptide formed by monocarboxypeptidase which removes the amino acid from C-terminus of Ang I to form the biologically active peptide Ang (1-9), which is further cleaved to form Ang (1-7) through ACE and NEP (Neutral endopeptidase) hydrolysis reaction. In addition to this reaction Ang (1-7) can also directly formed from Ang II via cleavage of C-terminus Phenylalanine residue to form physiologically and biologically more relevant Ang (1-7). Discovery of Ang (1-7) antagonist A779, confirmed the existence of G-protein coupled Mas receptor for the function of Ang (1-7) and suggested that this peptide exerts its effects by binding to the receptor distinct from the AT1 and AT2 receptors. Researchers have confirmed that ANG (1-7)/ACE-2/Mas axis is likely acting as a counter-regulatory axis to counteract the deleterious effects of ACE/ANG II/ AT1 receptor axis. Ang (1-7) is subsequently metabolized into the Ang (1-5) by ACE and ACE2 is capable of further metabolizing peptides like

apelin-13, dynorphin, neurotensin, ghrelin and bradykinin. Very short half life of Ang (1-7) is found in rat experiments. ACE 2 shares around 42% homology with ACE and it is monocarboxy peptidase with 805 amino acids. ACE2 is ectoenzyme and is expressed in the heart, kidney, testes, liver, lung, brain and small intestine. Ang (1-7) was found in aortic root, coronary sinus, and right atrium and its level is reduced with ACE inhibitor. Ang (1-7) decreases the arterial blood pressure and is involved in the synthesis and release of vasopressin. In case of heart, Ang (1-7) stimulates antiarrythmogenic effects, dilates the arteries and increase the blood flow, and also affects the cardiac contractility. ACE-2 knockout mice showed enhanced levels of ANG II and increased hypoxia inducible genes, reduced cardiac contractility, a decrease in the aortic and ventricular pressure, and a thinning of the left ventricular wall. Ang (1-7) protects from all these effects by preventing the development of cardiac hypertrophy and fibrosis and these effects are independent of blood pressure reduction effects of Ang (1-7). The orphan heterotrimeric MAS receptor (guanine nucleotide binding protein coupled receptor) is the functional binding receptor for the Ang (1-7).