Aldosterone and mineralocorticoid receptors: orphan questions

Classically, mineralocorticoid receptors (MR) are activated by aldosterone to promote unidirectional transepithelial sodium transport. Activation of MR in nonepithelial tissues has been shown to elevate blood pressure (central nervous system; CNS) and to cause hypertrophy and fibrosis (heart). For both epithelial and nonepithelial tissues, there remain a variety of questions regarding MR which are not only unanswered but also essentially not addressed. Seven such questions include: (1) how the physiologic glucocorticoids (cortisol and corticosterone) can mimic aldosterone action in epithelial MR, but act as antagonists in the heart and AV3V region; (2) how salt facilitates the nonepithelial, pathophysiologic effects of aldosterone; (3) how aldosterone activates unprotected AV3V MR in the face of orders of magnitude higher circulating glucocorticoid concentrations; (4) how unprotected nonepithelial MR act as "always occupied" receptors in guinea pigs and other species; (5) how, when 11beta hydroxysteroid dehydrogenase type 2 is active, epithelial MR occupied by physiologic glucocorticoids appear transcriptionally inactive; (6) how aldosterone activates epithelial MR in the face of approximately 103-fold higher glucocorticoid levels, plasma binding and 11beta hydroxysteroid dehydrogenase type 2 activity notwithstanding; and (7) how aldosterone produces changes in urinary [K+] before [Na+].