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).
Organ Systems
endocrine
cardiovascular
renal
Pathway Steps
angiotensin II + ↑[K⁺] + ACTH → aldosterone synthesis (zona glomerulosa) — via CYP11B2 (aldosterone synthase) — rate-limiting; KCNJ5 mutations → primary aldosteronism. Aldosterone is made in the adrenal zona glomerulosa, driven chiefly by angiotensin II (via the renin-angiotensin system) and by rising plasma K⁺, with ACTH only a minor acute stimulus. This dual control lets aldosterone serve both volume/blood-pressure regulation (via AngII) and potassium homeostasis.
aldosterone → MR (cytoplasmic → nuclear) — via kidney + colon: 11β-HSD2 protects from cortisol cross-activation. Aldosterone, being lipophilic, enters cells and binds the cytoplasmic mineralocorticoid receptor, which sheds chaperones and translocates to the nucleus as a ligand-activated transcription factor. As a steroid receptor, the MR works over hours — the “genomic” phase of aldosterone action.
MR-aldosterone → SGK1 induction (early) — via → ENaC trafficking + Na/K-ATPase activity in DCT/CD. An early MR target is SGK1, a kinase that stabilizes ENaC at the membrane (by phosphorylating the ubiquitin ligase Nedd4-2). SGK1 induction is among the fastest transcriptional responses, giving the rapid arm of aldosterone’s effect on sodium transport before slower channel synthesis.
MR-aldosterone → ENaC αβγ + ROMK transcription — via → apical Na⁺ entry + basolateral K⁺ secretion. MR drives transcription of the epithelial sodium channel (ENaC α/β/γ) and the potassium channel ROMK in the distal nephron, increasing Na⁺ reabsorption and K⁺ secretion. This is the core action that expands volume and raises blood pressure — and the step blocked by amiloride (ENaC) and by MR antagonists.
cortisol + 11β-HSD2 deficiency / licorice → MR over-activation (AME) — via → hypokalemic hypertension. The MR is not aldosterone-selective: cortisol binds it equally, and selectivity depends on 11β-HSD2 converting cortisol to inactive cortisone in MR cells. When this enzyme fails (genetic AME) or is inhibited (licorice/glycyrrhetinic acid), cortisol floods the MR — causing hypertension and hypokalemia from apparent mineralocorticoid excess.
extra-renal MR (heart, vessels) → fibrosis + endothelial dysfunction — via maladaptive remodeling in HFrEF — basis for MRA benefit beyond Na handling. MR is also expressed in heart, vasculature, and immune cells, where chronic activation drives fibrosis, inflammation, and endothelial dysfunction independent of blood pressure. This is the rationale for MR antagonists (spironolactone, eplerenone, finerenone) in heart failure and diabetic kidney disease.