Pendrin regulates ENaC abundance and function by modulating luminal HCO3− concentration

Abstract

Pendrin regulates abundance and function of the epithelial Na+ channel, ENaC, in kidney. Since pendrin mediates HCO3− secretion we hypothesized that ENaC is regulated by changes in luminal HCO3− concentration. Thus mice received either aldosterone with a NaCl‐replete diet containing NaHCO3 to increase pendrin‐dependent HCO3− secretion or aldosterone, diet and acetazolamide to increase luminal HCO3− concentration through a pendrin‐independent mechanism. ENaC abundance and function were lower in pendrin null relative to wild type mice when given aldosterone alone. However, when acetazolamide was added ENaC abundance and function were similar in wild type and pendrin null mice. To determine if HCO3− concentration has a direct effect on ENaC abundance and function, amiloride‐sensitive current and ENaC subunit abundance were measured in mpkCCD cells, a mouse principal cell line. ENaC‐mediated current and subunit abundance rose with increased HCO3− concentration on the apical or basolateral side achieved by substitution with either Cl− or methanesulfonate. However, ENaC was more sensitive to changes in HCO3− concentration on the basolateral than the apical side. We conclude that pendrin modulates ENaC abundance and function, at least in part, by raising luminal HCO3−concentration and/or pH. Extracellular HCO3− concentration likely modulates ENaC function through an intracellular signaling event.