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This Article Full Text Full Text (PDF) All Versions of this Article: 295/5/G909    most recent 90312.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Musch, M. W. Articles by Chang, E. B. PubMed PubMed Citation Articles by Musch, M. W. Articles by Chang, E. B.

MUCOSAL BIOLOGY

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

The Martin Boyer Laboratories, Department of Medicine, University of Chicago, Chicago, Illinois

Submitted 29 April 2008 ; accepted in final form 16 September 2008

Aldosterone-induced intestinal Na⁺ absorption is mediated by increased activities of apical membrane Na⁺/H⁺ exchange (aNHE3) and basolateral membrane Na⁺-K⁺-ATPase (BLM-Na⁺-K⁺-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 -subunit of BLM-Na⁺-K⁺-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⁺-K⁺-ATPase. Ouabain inhibition of the early increase in aldosterone-induced Na⁺-K⁺-ATPase activation blocked most of the apical NHE3 insertion, possibly by inhibiting Na⁺-K⁺-ATPase-induced changes in intracellular sodium concentration ([Na]_i). Over the next 6–48 h, further increases in aNHE3 and BLM-Na⁺-K⁺-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⁺ absorption involves two phases. The first phase involves stimulation of PI3K, which increases SGK-dependent insertion and function of BLM-Na⁺-K⁺-ATPase and subsequent increased membrane insertion of aNHE3. The latter may be caused by Na⁺-K⁺-ATPase-induced changes in [Na] or transcellular Na flux. The second phase involves SGK-dependent increases in total NHE3 and Na⁺-K⁺-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.

Na⁺ transport; intestine; intracellular Na⁺, intestinal adaptation; fluid and electrolyte transport; diarrhea; malabsorption; Na⁺-H⁺ exchange