Aldosterone Regulates Pendrin and Epithelial Sodium Channel Activity through Intercalated Cell Mineralocorticoid Receptor–Dependent and –Independent Mechanisms over a Wide Range in Serum Potassium
Authors: Pham Truyen D. , Verlander Jill W. , Wang Yanhua , Romero Cesar A. , Yue Qiang , Chen Chao , Thumova Monika , Eaton Douglas C. , Lazo-Fernandez Yoskaly , Wall Susan M. 
Published: February 2020

Significance Statement
The mineralocorticoid receptor within intercalated cells increases chloride transport in the mouse cortical collecting duct (CCD) through a mechanism involving the apical chloride/bicarbonate exchanger pendrin. In mouse studies, the authors demonstrated that ablating this receptor in intercalated cells markedly changes pendrin’s total abundance and subcellular distribution through a direct effect of the receptor, which occurs over a wide range in serum potassium concentration. The mineralocorticoid receptor within intercalated cells also indirectly modulates sodium channel activity in principal cells. Aldosterone increases pendrin through mechanisms both dependent and independent of the receptor. These data suggest that mineralocorticoid receptor antagonists increase NaCl excretion by the kidney, in part, by inhibiting intercalated cell pendrin-mediated chloride absorption directly and by inhibiting epithelial sodium channel–mediated sodium absorption indirectly through an effect of intercalated cell receptor blockade.

Background
Aldosterone activates the intercalated cell mineralocorticoid receptor, which is enhanced with hypokalemia. Whether this receptor directly regulates the intercalated cell chloride/bicarbonate exchanger pendrin is unclear, as are potassium’s role in this response and the receptor’s effect on intercalated and principal cell function in the cortical collecting duct (CCD).

Methods
We measured CCD chloride absorption, transepithelial voltage, epithelial sodium channel activity, and pendrin abundance and subcellular distribution in wild-type and intercalated cell–specific mineralocorticoid receptor knockout mice. To determine if the receptor directly regulates pendrin, as well as the effect of serum aldosterone and potassium on this response, we measured pendrin label intensity and subcellular distribution in wild-type mice, knockout mice, and receptor-positive and receptor-negative intercalated cells from the same knockout mice.

Results
Ablation of the intercalated cell mineralocorticoid receptor in CCDs from aldosterone-treated mice reduced chloride absorption and epithelial sodium channel activity, despite principal cell mineralocorticoid receptor expression in the knockout mice. With high circulating aldosterone, intercalated cell mineralocorticoid receptor gene ablation directly reduced pendrin’s relative abundance in the apical membrane region and pendrin abundance per cell whether serum potassium was high or low. Intercalated cell mineralocorticoid receptor ablation blunted, but did not eliminate, aldosterone’s effect on pendrin total and apical abundance and subcellular distribution.

Conclusions
With high circulating aldosterone, intercalated cell mineralocorticoid receptor ablation reduces chloride absorption in the CCD and indirectly reduces principal cell epithelial sodium channel abundance and function. This receptor directly regulates pendrin’s total abundance and its relative abundance in the apical membrane region over a wide range in serum potassium concentration. Aldosterone regulates pendrin through mechanisms both dependent and independent of the IC MR receptor.