Aldosterone regulation of intestinal Na absorption involves SGK-mediated changes in NHE3 and Na[sup+] pump activity.

-Aldosterone-induced intestinal Na[sup+] absorption is mediated by increased activities of apical membrane Na[sup+]/H[sup+] exchange (aNHE3) and basolateral membrane Na[sup+]-K[sup+]- ATPase (BLM-Na[sup+]-K[sup+]-ATPase) activities. Because the processes coordinating these events were not well understood, we investigated human intestinal Caco-2BBE cells where aldosterone increases within 2-4 h of aNHE3 and a-subunit of BLM-Na[sup+]-K[sup+]-ATPase, but not total abundance of these proteins. Although aldosterone activated Akt2 and serum glucorticoid kinase-1 (SGK-1), the latter through stimulation of phosphatidylinositol 3-kinase (PI3K), only the SGK-1 pathway mediated its effects on Na[sup+]-K[sup+]-ATPase. Ouabain inhibition of the early increase in aldosterone-induced Na[sup+]-K[sup+]-ATPase activation blocked most of the apical NHE3 insertion, possibly by inhibiting Na[sup+]-K[sup+]-ATPase-induced changes in intracellular sodium concentra- tion ([Na]1). Over the next 6-48 h, further increases in aNHE3 and BLM-Na[sup+]-K[sup+]-ATPase activity and total protein expression were observed to be largely mediated by aldosterone-activated SGK-1 pathway. Aldosterone-induced increases in NHE3 mRNA, for instance, could be inhibited by RNA silencing of SGK-1, but not Akt2. Additionally, aldosterone-induced increases in NHE3 promoter activity were blocked by silencing SGK-1 as well as pharmacological inhibition of PI3K. In conclusion, aldosterone-stimulated intestinal Na[sup+] absorption involves two phases. The first phase involves stimulation of PI3K, which increases SGK-dependent insertion and function of BLM-Na[sup+]-K[sup+]-ATPase and subsequent increased membrane insertion of aNHE3. The latter may be caused by Na[sup+]-K[sup+]-ATPase-induced changes in [Na] or transcellular Na flux. The second phase involves SOK-dependent increases in total NHE3 and Na[sup+]-K[sup+]-ATPase protein expression and activities. The coordination of apical and BLM transporters after aldosterone stimulation is therefore a complex process that requires multiple time- and interdependent cellular processes. [ABSTRACT FROM AUTHOR]