Epithelial sodium channel regulated by aldosterone-induced protein sgk

Sodium homeostasis in terrestrial and freshwater vertebrates is controlled by the corticosteroid hormones, principally aldosterone, which stimulate el ectrogenic Na+ absorption in tight epithelia. Although aldosterone is known to increase apical membrane Na+ permeability in target cells through chang es in gene transcription, the mechanistic basis of this effect remains poor ly understood. The predominant early effect of aldosterone is to increase t he activity of the epithelial sodium channel (ENaC), although ENaC mRNA and protein levels do not change initially. Rather, the open probability and/o r number of channels in the apical membrane are greatly increased by unknow n modulators. To identify hormone-stimulated gene products that modulate EN aC activity, a subtracted cDNA library was generated from A6 cells, a stabl e cell line of renal distal nephron origin, and the effect of candidates on ENaC activity was tested in a coexpression assay. We report here the ident ification of sgk (serum and glucocorticoid-regulated kinase), a member of t he serine-threonine kinase family as an aldosterone-induced regulator of EN aC activity. sgk mRNA and protein were strongly and rapidly hormone stimula ted both in A6 cells and in rat kidney. Furthermore, sgk stimulated ENaC ac tivity approximately 7-fold when they were coexpressed in Xenopus laevis oo cytes. These data suggest that sgk plays a central role in aldosterone regu lation of Na+ absorption and thus in the control of extracellular fluid vol ume, blood pressure, and sodium homeostasis.