SGK integrates insulin and mineralocorticoid regulation of epithelial sodium transport.
The epithelial Na+ channel (ENaC) constitutes the rate-limiting step for Na+ transport across tight epithelia and is the principal target of hormonal regulation, particularly by insulin and mineralocorticoids. Recently, the serine-threonine kinase (SGK) was identified as a rapidly mineralocorticoid-responsive gene, the product of which stimulates ENaC-mediated Na+ transport. Like its close relative, protein kinase B (also called Akt), SGK's kinase activity is dependent on phosphatidylinositol 3-kinase (PI3K), a key mediator of insulin signaling. In our study we show that PI3K is required for SGK-dependent stimulation of ENaC-mediated Na+ transport as well as for the production of the phosphorylated form of SGK. In A6 kidney cells, mineralocorticoid induction of the phosphorylated form of SGK preceded the increase in Na+ transport, and specific inhibition of PI3K inhibited both phosphorylation of SGK and mineralocorticoid-induced Na+ transport. Insulin both augmented SGK phosphorylation and synergized with mineralocorticoids in stimulating Na+ transport. In a Xenopus laevis oocyte coexpression assay, SGK-stimulated ENaC activity was also markedly reduced by PI3K inhibition. Finally, in vitro-translated SGK specifically interacted with the ENaC subunits expressed in Escherichia coli as glutathione S-transferase fusion proteins. These data suggest that SGK is a PI3K-dependent integrator of insulin and mineralocorticoid actions that interacts with ENaC subunits to control Na+ entry into kidney collecting duct cells.
Wang
J
J
Division of Nephrology, Department of Medicine, and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco 94143, USA.
Barbry
P
P
Maiyar
A C
AC
Rozansky
D J
DJ
Bhargava
A
A
Leong
M
M
Firestone
G L
GL
Pearce
D
D
D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D017874:Immediate-Early Proteins; D007328:Insulin / Q000494:pharmacology; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008901:Mineralocorticoids / Q000494:pharmacology; D009687:Nuclear Proteins; D010455:Peptides / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D026941:Sodium Channel Blockers; D015222:Sodium Channels / Q000378:metabolism*; D014982:Xenopus laevis; D000099184:Serum-Glucocorticoid Regulated Kinases
D004791:Enzyme Inhibitors; D017874:Immediate-Early Proteins; D007328:Insulin; D008901:Mineralocorticoids; D009687:Nuclear Proteins; D010455:Peptides; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D000099184:Serum-Glucocorticoid Regulated Kinases; C029311:serum sodium transport inhibitor