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.