Aldosterone Research: 65 Years, and Counting.

Aldosterone was characterized as the major mineralocorticoid hormone 65 years ago, and since then its physiologic role in epidural electrolyte homeostasis the province of nephrologists. In epithelia it acts via the mineralocorticoid receptor (MR) to retain Na and excrete K; MRs, however, are widely expressed in organs not known to be aldosterone target tissues. MRs are not merely "aldosterone receptors," as they have equivalently high affinity for the physiologic glucocorticoids, and for progesterone. In epithelia (plus in the blood vessel wall and in the nucleus tractus solitarius of the brain) MRs are "protected" by coexpression of the enzyme 11β-hydroxysteroid dehydrogenase. This enzyme converts cortisol-which circulates at much higher concentrations than aldosterone-to receptor-inactive cortisone, thus allowing aldosterone selectively to activate "protected" MR. In tissues which do not express 11β-hydroxysteroid dehydrogenase, the default MR ligand is cortisol, which circulates at ≥100-fold higher plasma free concentrations than aldosterone. In such tissues there is as yet scant evidence for the physiologic role of cortisol-occupied MR: over the past decade, however, it has become clear that in damaged tissues cortisol can act as an MR-agonist, mimicking the effects seen with aldosterone under experimental conditions, in vitro and in vivo. Many pathophysiologic roles have been attributed to aldosterone: on the current evidence there are none outside its long established epithelial actions, those on the blood vessel wall and on the nucleus tractus solitarius.