Nongenomic Actions of Aldosterone on the Renal Tubule

Aldosterone plays a major role in the maintenance of sodium, potassium, and acid-base balance through its effects on renal electrolyte excretion. This regulation is achieved through aldosterone-induced stimulation of Na+ absorption, K+ secretion, and H+ secretion by the distal nephron, particularly segments of the collecting duct.1–3 These classical actions are mediated through binding of aldosterone to the intracellular mineralocorticoid receptor (MR). The hormone-receptor complex translocates to the nucleus, where it promotes gene transcription and the production of proteins that modulate the expression and activity of the epithelial Na+ channel (ENaC) and other ion transport proteins.1,4–6 Regulatory actions of aldosterone via the MR play an important role in the normal maintenance of blood pressure but also have been implicated in the pathogenesis of hypertension and the progression of renal disease.6–9In addition to their classical actions, aldosterone and other steroid hormones influence cell processes through nongenomic mechanisms.10,11 Nongenomic effects of aldosterone have been demonstrated in many different epithelial and nonepithelial tissues and are defined by (1) an insensitivity to inhibitors of transcription (actinomycin D) and translation (cycloheximide) and (2) a rapid time course (seconds to a few minutes) that is incompatible with gene regulation and de novo protein synthesis. A rapid onset of action is a sufficient but not necessary criterion for a nongenomic effect. Some nongenomic effects can occur with a slower time course. An additional feature often associated with nongenomic effects is that they are not blocked by spironolactone and/or other MR antagonists, consistent with mediation via a nonclassical aldosterone receptor.10,11 Although compelling evidence exists for rapid effects of aldosterone unrelated to the MR, a novel aldosterone receptor for nongenomic regulation has not been identified, and there is evidence that nongenomic actions of aldosterone can be mediated via the classical …