SGK integrates insulin and mineralocorticoid regulation of epithelial sodium transport

被引:182
作者
Wang, J
Barbry, P
Maiyar, AC
Rozansky, DJ
Bhargava, A
Leong, M
Firestone, GL
Pearce, D
机构
[1] Univ Calif San Francisco, Dept Med, Div Nephrol, San Francisco, CA 94143 USA
[2] Univ Calif San Francisco, Dept Mol & Cellular Pharmacol, San Francisco, CA 94143 USA
[3] Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA
关键词
epithelial sodium channel; phosphatidylinositol; 3-kinase; serine-threonine kinase;
D O I
10.1152/ajprenal.2001.280.2.F303
中图分类号
Q4 [生理学];
学科分类号
071003 ;
摘要
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.
引用
收藏
页码:F303 / F313
页数:11
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