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 electrogenic Na+ absorption in tight epithelia. Although aldosterone is known to increase apical membrane Na+ permeability in target cells through changes in gene transcription, the mechanistic basis of this effect remains poorly understood. The predominant early effect of aldosterone is to increase the activity of the epithelial sodium channel (ENaC), although ENaC mRNA and protein levels do not change initially. Rather, the open probability and/or number of channels in the apical membrane are greatly increased by unknown modulators. To identify hormone-stimulated gene products that modulate ENaC activity, a subtracted cDNA library was generated from A6 cells, a stable 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 identification of sgk (serum and glucocorticoid-regulated kinase), a member of the serine-threonine kinase family, as an aldosterone-induced regulator of ENaC activity. sgk mRNA and protein were strongly and rapidly hormone stimulated both in A6 cells and in rat kidney. Furthermore, sgk stimulated ENaC activity approximately 7-fold when they were coexpressed in Xenopus laevis oocytes. These data suggest that sgk plays a central role in aldosterone regulation of Na+ absorption and thus in the control of extracellular fluid volume, blood pressure, and sodium homeostasis.
Chen
S Y
SY
Division of Nephrology, Departments of Medicine and Cellular and Molecular Pharmacology, Box 0532, University of California, San Francisco, CA 94143, USA.
Bhargava
A
A
Mastroberardino
L
L
Meijer
O C
OC
Wang
J
J
Buse
P
P
Firestone
G L
GL
Verrey
F
F
Pearce
D
D
D000450:Aldosterone / Q000494:pharmacology / Q000502:physiology*; D000818:Animals; D002460:Cell Line; D003001:Cloning, Molecular; D053503:Epithelial Sodium Channels; D005260:Female; D006801:Humans; D017874:Immediate-Early Proteins; D015640:Ion Channel Gating / Q000502:physiology; D007668:Kidney; D008969:Molecular Sequence Data; D009687:Nuclear Proteins; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000235:genetics / Q000502:physiology*; D014982:Xenopus laevis; D000099184:Serum-Glucocorticoid Regulated Kinases
D000450:Aldosterone; D053503:Epithelial Sodium Channels; D017874:Immediate-Early Proteins; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D011994:Recombinant Proteins; D012964:Sodium; D015222:Sodium Channels; D000099184:Serum-Glucocorticoid Regulated Kinases