renin-angiotensin system

**Cascade** - Angiotensinogen (liver, constitutively made) is cleaved by **renin** (from juxtaglomerular [JG] cells of the afferent arteriole) to **angiotensin I** (inactive). - **ACE** (angiotensin-converting enzyme, mainly on pulmonary capillary endothelium) converts angiotensin I to **angiotensin II (Ang II)**. ACE also degrades **bradykinin**.

**Stimuli for renin release** 1. ↓ Renal perfusion pressure (baroreceptors in the afferent arteriole), as in hypotension, hemorrhage, or renal artery stenosis. 2. ↓ NaCl delivery to the macula densa (distal tubule). The macula densa signals the JG cells. 3. ↑ Sympathetic tone via β1 receptors on JG cells. - Renin release is inhibited by Ang II (negative feedback), ANP, and increased afferent arteriolar pressure.

**Actions of Ang II (AT1 receptor, Gq)** - Vasoconstriction of arterioles, with preferential efferent arteriole constriction. This ↑ systemic vascular resistance and BP, and ↑ GFR/filtration fraction (FF = GFR/RPF). - ↑ **Aldosterone** secretion from the zona glomerulosa. This ↑ Na+ reabsorption (ENaC) and K+/H+ secretion in the principal and α-intercalated cells of the collecting duct, so volume expands, and the system can cause hypokalemia and metabolic alkalosis. - ↑ Na+/H+ exchange in the proximal tubule, which ↑ Na+ and HCO3- reabsorption (contraction alkalosis). - ↑ **ADH** release from the posterior pituitary. - Stimulates **thirst** (hypothalamus). - Cardiac and vascular remodeling (hypertrophy, fibrosis) with chronic activation.

**Clinical correlations** - **ACE inhibitors** (-pril): ↓ Ang II and ↑ bradykinin. Adverse effects: dry cough, angioedema, hyperkalemia, teratogenicity (fetal renal malformations), AKI in bilateral renal artery stenosis, and ↑ creatinine from lower efferent tone. They are contraindicated in pregnancy. Benefits: HTN, HFrEF, post-MI, and diabetic nephropathy (slow progression by dilating efferent arterioles). - **ARBs** (-sartan): block AT1. They have the same effects as ACE inhibitors but no cough or angioedema, because bradykinin is not ↑ (use them in ACE inhibitor intolerance). - **Aliskiren**: direct renin inhibitor. - **Aldosterone antagonists** (spironolactone, eplerenone): hyperkalemia. Spironolactone can cause gynecomastia. - **Renovascular HTN** (renal artery stenosis from atherosclerosis in older patients or fibromuscular dysplasia in young women): the stenotic kidney is hypoperfused, so ↑ renin, and the contralateral kidney is suppressed. Look for an abdominal bruit and "string of beads" on imaging in fibromuscular dysplasia. - **Primary hyperaldosteronism (Conn)**: ↑ aldosterone with **↓ renin** (HTN, hypokalemia, metabolic alkalosis). Secondary hyperaldosteronism (CHF, cirrhosis, nephrotic syndrome, renal artery stenosis) has **↑ renin**. - **Juxtaglomerular cell tumor (reninoma)**: ↑ renin, HTN, hypokalemia. - **Heart failure**: chronic RAAS activation is maladaptive, which is why ACE inhibitors, ARBs, ARNI (sacubitril/valsartan), and MRAs improve mortality. - **Sacubitril** (neprilysin inhibitor) ↑ natriuretic peptides and bradykinin, and is combined with valsartan. It is contraindicated with ACE inhibitors (angioedema risk). - **NSAIDs** blunt prostaglandin-mediated afferent dilation, so in volume depletion with ACE inhibitor/ARB use ("triple whammy" with diuretics) they raise the risk of AKI. - **Opposing system**: ANP/BNP (↑ GFR, ↓ renin, natriuresis).

**High-yield pearls** - Ang II constricts the efferent arteriole: ↑ GFR, ↑ FF, ↓ RPF. ACE inhibitors and ARBs reverse this (↓ GFR, ↓ FF). - Ang II is the main stimulus for aldosterone (along with hyperkalemia). Renin is the rate-limiting step. - Renin is ↑ in renal artery stenosis, hemorrhage, dehydration, cirrhosis, and heart failure, and ↓ in primary hyperaldosteronism and in HTN from volume excess.