Category: receptor_pharmacology
The mineralocorticoid receptor (MR, NR3C2) is a steroid nuclear receptor canonically activated by aldosterone in the kidney distal nephron, where it drives Na⁺ retention + K⁺ excretion. Mechanism: aldosterone diffuses across the basolateral membrane → binds MR (in DCT/CD principal cells) → MR translocates to nucleus → induces SGK1, ENaC (αβγ subunits), Na⁺/K⁺-ATPase, ROMK → net Na⁺ reabsorption + K⁺ secretion. Critical 11β-HSD2 selectivity: aldosterone and cortisol bind MR with similar affinity, but kidney + colon co-express 11β-HSD2 which inactivates cortisol to cortisone, allowing aldosterone selectivity. 11β-HSD2 deficiency or licorice (glycyrrhetinic acid) inhibition → "apparent mineralocorticoid excess" — cortisol drives MR → hypokalemic HTN. Extra-renal MR is now recognized in heart (cardiomyocytes + fibroblasts → maladaptive fibrosis), vasculature (endothelial dysfunction, vascular inflammation), brain (neurons → BP regulation + mood), adipocytes (inflammation). Clinical: aldosterone-driven heart failure (RALES/EPHESUS), resistant hypertension (PATHWAY-2), primary aldosteronism (Conn's). Drugs: steroidal MRAs — spironolactone (non-selective; off-target androgen + progesterone receptors → gynecomastia + impotence); eplerenone (selective MR; better-tolerated but less potent); canrenone (active spironolactone metabolite). Non-steroidal MRA — finerenone (FIDELIO-DKD + FIGARO-DKD — slows CKD progression in T2D; selective without sex-hormone side effects); esaxerenone (Japan). SGLT2 inhibitors lower aldosterone modestly + synergize with MRA in CKD. Cross-links: [[raas_axis]] (aldosterone synthesis upstream), [[renal_tubular_transport]] (downstream Na/K handling).