the renin

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The renin-angiotensin-aldosterone system (RAAS) plays an important role in regulatingblood

volume andsystemic vascular resistance, which together influencecardiac output andarterial pressure. As

the name implies, there are three important components to this system: 1) renin, 2) angiotensin, and 3)

aldosterone. Renin, which is primarily released by the kidneys, stimulates the formation of angiotensin in

blood and tissues, which in turn stimulates the release of aldosterone from the adrenal cortex.

Renin is a proteolytic enzyme that is released into the circulation primarily by the kidneys. Its release is

stimulated by:

1. sympathetic nerve activation (acting through 1-adrenoceptors)

2. renal artery hypotension (caused by systemic hypotension or renal artery stenosis)

3. Decreased sodium delivery to the distal tubules of the kidney.

Juxtaglomerular (JG) cellsassociated with the afferent arteriole entering the renal glomerulus are the

primary site of renin storage and release. A reduction in afferent arteriole pressure causes the release of

renin from the JG cells, whereas increased pressure inhibits renin release. Beta1-adrenoceptors located on the

JG cells respond to sympathetic nerve stimulation by releasing renin. Specialized cells (macula densa) of

distal tubules lie adjacent to the JG cells of the afferent arteriole. The macula densa senses the concentration

of sodium and chloride ions in the tubular fluid. When NaCl is elevated in the tubular fluid, renin release is

inhibited. In contrast, a reduction in tubular NaCl stimulates renin release by the JG cells. There is evidence

thatprostaglandins (PGE2and PGI2) stimulate renin release in response to reduced NaCl transport across the

macula densa. When afferent arteriole pressure is reduced, glomerular filtration decreases, and this reduces

NaCl in the distal tubule. This serves as an important mechanism contributing to the release of renin when

there is afferent arteriole hypotension, which can be caused by systemic hypotension or narrowing (stenosis)

of the renal artery that supplies blood flow to the kidney.

When renin is released into the blood, it acts upon a circulating substrate, angiotensinogen, that undergoes

proteolytic cleavage to form the decapeptide angiotensin I. Vascular endothelium, particularly in the lungs,

has an enzyme,angiotensin converting enzyme (ACE), that cleaves off two amino acids to form the

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octapeptide, angiotensin II (AII), although many other tissues in the body (heart, brain, vascular) also can

form AII.

AII has several very important functions:

Constricts resistance vessels (viaAII [AT1] receptors) thereby increasingsystemic vascular

resistance andarterial pressure

Stimulates sodium transport (reabsorption) at several renal tubular sites, thereby increasing

sodium and water retention by the body

Acts on the adrenal cortex to releasealdosterone, which in turn acts on the kidneys to

increase sodium and fluid retention

Stimulates the release ofvasopressin (antidiuretic hormone, ADH) from the posterior

pituitary, which increases fluid retention by the kidneys

Stimulates thirst centers within the brain

Facilitatesnorepinephrine release fromsympathetic nerveendings and inhibitsnorepinephrine re-uptake by nerve endings, thereby enhancing sympathetic adrenergic

function

Stimulatescardiac hypertrophy and vascular hypertrophy

The renin-angiotensin-aldosterone pathway is not only regulated by the mechanisms that stimulate renin

release, but it is also modulated bynatriuretic peptides (ANP and BNP) released by the heart. These

natriuretic peptides acts as an important counter-regulatory system.

Therapeutic manipulation of this pathway is very important in treatinghypertension andheart failure.ACE

inhibitors,AII receptor blockers andaldosterone receptor blockers,for example, are used to decrease arterial

pressure, ventricular afterload, blood volume and hence ventricular preload, as well as inhibit and reversecardiac and vascular hypertrophy.