Renin-angiotensin-aldosterone axis

Category: endocrine_axis

Overview

Major blood-pressure + volume homeostasis loop. Renin (from JG cells) cleaves liver-derived angiotensinogen to angiotensin I (decapeptide, inactive). ACE (pulmonary endothelium) cleaves AT-I to angiotensin II (octapeptide, potent vasoconstrictor + aldosterone secretagogue). AT-II → AT1 receptor (vasculature, adrenal cortex) → systemic vasoconstriction + aldosterone release. Aldosterone acts on the distal tubule + collecting duct via MR to increase Na+/H2O reabsorption + K+/H+ excretion. ACEi block ACE; ARBs block AT1; MRAs (spironolactone, eplerenone) block aldosterone receptor; direct renin inhibitors (aliskiren) block the first step.

Organ Systems

• cardiovascular
• renal
• endocrine

Pathway Steps

1. angiotensinogen → angiotensin-i — via renin (JG cells) — first-step rate-limiting; ALISKIREN TARGET. The liver constitutively secretes angiotensinogen, which renin — released by the kidney in response to low perfusion, low sodium, or sympathetic drive — cleaves to angiotensin I. Renin release is the rate-limiting, regulated step of the system, and the target of direct renin inhibitors (aliskiren).
2. angiotensin-i → angiotensin-ii — via ACE (angiotensin-converting enzyme, pulmonary endothelium) — ACEi TARGET. Angiotensin-converting enzyme (ACE), mainly in the lung, converts inactive angiotensin I to active angiotensin II. ACE also degrades bradykinin — which is why ACE inhibitors both lower angiotensin II and cause bradykinin-mediated cough/angioedema, whereas ARBs instead block the AT1 receptor downstream.
3. angiotensin-ii → aldosterone — via AT1 receptor on adrenal zona glomerulosa — ARB TARGET (upstream). Angiotensin II raises blood pressure directly (vasoconstriction) and indirectly by stimulating adrenal aldosterone release, which drives renal sodium and water retention. This volume/pressure-raising output is the core of the RAAS — and the reason its blockade is central to hypertension, heart failure, and CKD.

Known Modulators

• lisinopril (inhibitor) — ACE
• ramipril (inhibitor) — ACE
• enalapril (inhibitor) — ACE
• losartan (inhibitor) — AT1 receptor (also weak XO inhibitor)
• valsartan (inhibitor) — AT1 receptor
• telmisartan (inhibitor) — AT1 receptor (longest t½ ARB; partial PPAR-γ agonist)
• spironolactone (inhibitor) — mineralocorticoid receptor (also AR + progesterone receptor — gynecomastia)
• eplerenone (inhibitor) — mineralocorticoid receptor (more selective than spironolactone)
• captopril (inhibitor) — ACE. first oral ACE-i; short t½ (qid); SH group → unique cough/taste/skin side effects
• fosinopril (inhibitor) — ACE. dual hepatic + renal clearance — preferred in CKD over purely renally-cleared ACE-i
• quinapril (inhibitor) — ACE
• trandolapril (inhibitor) — ACE
• candesartan (inhibitor) — AT-1 receptor. tight AT-1 binding → strong + sustained BP effect; migraine prophylaxis off-label
• irbesartan (inhibitor) — AT-1 receptor
• olmesartan (inhibitor) — AT-1 receptor. sprue-like enteropathy boxed warning; rare but reversible on discontinuation
• methyldopa (activator) — central α2 (after AADC conversion to α-methyl-NE). pre-ARB-era central antihypertensive; pregnancy HTN gold standard for decades; hemolytic anemia risk

References

• PMID 17970613
• PMID 18378520