Renin-angiotensin-aldosterone system (RAAS)

Operative pathway regulating vascular volume, salt and water retention.

In heart failure decreased cardiac output and reduced renal perfusion leads to stimulation of plasma renin activity and thus to release of angiotensin II and aldosterone.

When decreased blood flow due to the low volume is recognized by kidney cells they secrete the enzyme renin. 


Renin then enters the blood where it catalyzes a protein called angiotensinogen to angiotensin I. 

The liver secretes inactive angiotensinogen, which is converted by renally secreted renin to angiotensin I.

Angiotensinogen is encoded by the gene AGT, and is a glycoprotein secreted by hepatocytes that is cleaved by renin to yield angiotensin I which is further cleave to generate angiotensin II.

Angiotensinogen is the rate limiting factor in the production of angiotensinII, and evidence links angiotensinogen and angiotensin II to hypertension: the greater the copy number of angiotensin heme, the higher the blood pressure.

Renin catalyzes inactive angiotensinogen to angiotensin I.

Renin is the first enzyme in the renin-angiotensin-aldosterone system.

Renin cleaves angiotensinogen to angiotensin I, which is in turn converted by angiotensin-converting enzyme (ACE) to angiotensin II.

Angiotensin II has both direct and indirect effects on blood pressure.

It directly causes arterial smooth muscle to contract, leading to vasoconstriction and increased blood pressure.

Angiotensin II also stimulates the production of aldosterone from the adrenal cortex, which causes the tubules of the kidneys to increase reabsorption of sodium, with water following, thereby increasing plasma volume, and thus also blood pressure.

Angiotensin I is converted by angiotensin-converting enzyme to angiotensin II, which is a powerful vasoconstrictor.

Angiotensin I is almost immediately converted by an enzyme present in the blood to the active form of the protein, angiotensin II. 


Angiotensin II reaches the posterior pituitary gland and the adrenal cortex, where it causes a cascade effect of hormones that cause the kidneys to retain water and sodium, increasing blood pressure.

Agiotensin-converting enzyme is secreted primarily by lung endothelium.

Angiotensin II binds to angiotensin I receptors and leads to increased blood pressure, sodium retention, heart fibrosis and remodeling, glomerular hypertension, proteinuria and glomerulosclerosis.

Angiotensin II can also bind to angiotensin II receptors, which can lead to antifibrotic and anti-inflammatory effects, counteracting effects of angiotensin I binding.

Angiotensin II receptors are more prevalent in the fetus and have their role in adults is not defined.

Both ACE inhibitors and ARBs retard the decline in GFR associated with proteinuria which suggests that the renin-angiotensin system plays a significant role in the pathogenesis of chronic renal disease.

Angiotensin II levels are not completely suppressed with ACE inhibition, a process known as angiotensin II escape.

Prolonged treatment with ACE inhibitors can lead to a partial escape of the renin-angiotensin system (RAS) via the ACE independent generation of angiotensin II by chymase, an enzyme secreted by the heart (Urata H).

Angiotensin receptor blockade binding to angiotensin I receptor is thought to prevent negative effects of angiotensin II escape and promtes binding of angiotensin II to other targets, such as angiotensin II receptors.

Since ACE inhibitors do not completely suppress angiotensin II production and its effects, a rationale has been set forth to use ACE inhibitors and ARB in combination for more complete blockade of the renin-angiotensin system.

Blockade of the renin-angiotensin-aldosterone system (RASS) with angiotensin-converting enzyme inhibition or angiotensin receptor blockade are central therapies for both renal  and cardiovascular protection in patients with chronic kidney disease.


Blockade of RAAS is renal protective in early and advanced CKD in patients with diabetes and non-diabetic nephropathies.


ACE inhibitors and ARBs are effective antihypertensives and have specific anti-proteinuric effects.

Activation of this system increases risk of premature cardiovascular events.

Progressive activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system contributes to chronic heart failure, including that which occurs after acute myocardial infarction.

Pharmacological inhibition of the RAAS improves cardiac structure, function and outcomes.

The natriuretic peptide system provides counter balance to the RAAS, enhancing natriuresis and vasodilation while decreasing fibrosis and apoptosis.

Activation of this system increases the risk of myocardial infarction.

Activation of this system in the presence of hypertension is associated with an increased risk of myocardial infarction and stroke.

Plasma renin activity can be stimulated by diuretics, norepinephrine, hyponatremia and volume contraction.

Aldosterone is a mineralcorticoid predominantly secreted by the adrenal cortex in response to angiotensin II stimulation, hyperkalemia, and corticotropin.

Aldosterone hormone a fundamental role in intravascular volume and blood pressure homeostasis.
Through activation of the mineralcorticoid receptor, aldosterone may exert actions leading to organ damage in the heart, kidneys, and vasculature.
The successful use of the mineralcorticoid receptor antagonist Spironolactone in patients with resistant hypertension led to the conclusion that aldosterone may be the predominant underlying pathophysiologic cause of resisting hypertension through sodium retention.
Plasma aldosterone levels I significantly associate with hypertension as well as chronic kidney disease and metabolic syndrome.

Plasma aldosterone levels increase with the use of antihypertensive medications, and greater aldosterone levels are associated with lower circulating atrial natriuretic peptide levels.

Aldosterone is associated with water and salt retention and may lead to deposition of collagen in the cardiovascular system.

Aldosterone and cortisol bind to the mineralcorticoid receptor and link the powerful regulators of ion, salt, and water balance in the cortical collecting duct of the kidney with pressure, volume, and vasomotion in the cardiovascular system.

Adverse effects of aldosterone in congestive heart failure due to its mineralcorticoid properties leading to volume expansion and congestion, enhanced collagen deposition and negative remodeling.

Aldosterone system-adverse effects of aldosterone include increasing myocardial stiffness, hypokalemia, arrhythmias and inhibition of nitric oxide synthesis.

Aldosterone is a mediator of myocardial fibrosis, and blockade with spironolactone normalizes collagen contents in hypertrophic cardiomyopathy models

Correlation of high serum aldosterone levels and increased morbidity and mortality in patients with heart failure.

Aldosterone levels are increased in obesity.

Adipocytes can synthesize aldosterone directly or by secreting leptin, which stimulates the production of aldosterone by the adrenal gland.

Hyperaldosteronism leads to an expansion of plasma volume, which with normally functioning heart results in an increased cardiac output and blood pressure, but at the cost of increase in cardiac filling pressures.

Inhibition by ACE inhibitors and angiotensin II receptor blockers have renoprotective effects resulting from lowering blood pressure.

Low aldosterone levels are seen in diabetes mellitus and the use of ACE inhibitors or NSAIDs.

The renin angiotensin system activation may enhance erythropoiesis and may be associated with secondary erythrocytosis.

Zilebesiran is a small interfering RNA that silences hepatic AGT expression leading to a decrease in  production of angiotensinogen protein and suppresses synthesis of angiotensin I, and angiotensin II, and consequent blood pressure lowering.

Lorundrostat is a selective aldosterone synthetase inhibitor that provides targeted antihypertensive treatment for patients in whom aldosterone excess is contributing to clinical disease.

Lorundrostat decreases aldosterone production, rather than blocking the mineralocorticoid receptor, and may avoid adverse effects.

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