Differential Regulatory Activities of Potassium and Aldosterone in the Distal Nephron: A Resolution to the Aldosterone Paradox

Aldosterone has long been viewed as a master regulator of fluid and electrolyte homeostasis, acting through the mineralocorticoid receptor (MR) to stimulate electrogenic Na+ transport via the epithelial sodium channel (ENaC) in the distal nephron. This primary effect is thought to drive both K+ secretion and Cl- reabsorption; however, the underlying mechanism has remained obscure and the dual regulation has generated an enigma often referred to as the aldosterone paradox. Here we propose a model for regulated K+ secretion centered on local regulation of ENaC in the late distal convoluted tubule and early connecting tubule. In this segment, the MR is constitutively activated by glucocorticoids rather than by aldosterone, and yet ENaC activity and K+ secretion through the renal outer medullary K+ channel (ROMK) are not constitutive but, rather, are highly regulated. The model holds that the key regulatory step for K+ secretion involves a cell-autonomous mechanism through which local interstitial [K+] stimulates mechanistic target of rapamycin complex 2 (mTORC2)-dependent phosphorylation of the ENaC regulatory serum- and glucocorticoid-induced kinase 1 (SGK1); the K+-sensing kinase augments this phosphorylation by serving as a scaffold to enhance the physical interaction of mTORC2 with SGK1. Aldosterone acts further downstream to stimulate ENaC primarily in the late CNT and cortical collecting duct, in which ROMK apical expression is relatively low and Na+-Cl- reabsorption is favored. This revised paradigm resolves the aldosterone paradox and has important implications for hypertension, potassium disorders, and potentially medical therapies.