Nongenomic regulation by aldosterone of the epithelial NHE3 Na+/H+ exchanger

Abstract

The relevance of nongenomic pathways to regulation of epithelial function by aldosterone is poorly understood. Recently, we demonstrated that aldosterone inhibits transepithelial HCO(3)(-) absorption in the renal medullary thick ascending limb (MTAL) through a nongenomic pathway. Here, we examined the transport mechanism(s) responsible for this regulation, focusing on Na(+)/H(+) exchangers (NHE). In the MTAL, apical NHE3 mediates H(+) secretion necessary for HCO(3)(-) absorption; basolateral NHE1 influences HCO(3)(-) absorption by regulating apical NHE3 activity. In microperfused rat MTALs, the addition of 1 nM aldosterone rapidly decreased HCO(3)(-) absorption by 30%. This inhibition was unaffected by three maneuvers that inhibit basolateral Na(+)/H(+) exchange and was preserved in MTALs from NHE1 knockout mice, ruling out the involvement of NHE1. In contrast, exposure to aldosterone for 15 min caused a 30% decrease in apical Na(+)/H(+) exchange activity over the intracellular pH range from 6.5 to 7.7, due to a decrease in V(max). Inhibition of HCO(3)(-) absorption by aldosterone was not affected by 0.1 mM lumen Zn(2+) or 1 mM lumen DIDS, arguing against the involvement of an apical H(+) conductance or apical K(+)-HCO(3)(-) cotransport. These results demonstrate that aldosterone inhibits HCO(3)(-) absorption in the MTAL through inhibition of apical NHE3, and identify NHE3 as a target for nongenomic regulation by aldosterone. Aldosterone may influence a broad range of epithelial transport functions important for extracellular fluid volume and acid-base homeostasis through direct regulation of this exchanger.