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Am J Physiol Renal Physiol 280: F303-F313, 2001;
0363-6127/01 $5.00
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Vol. 280, Issue 2, F303-F313, February 2001

SGK integrates insulin and mineralocorticoid regulation of epithelial sodium transport

Jian Wang1,*, Pascal Barbry1,*, Anita C. Maiyar2, David J. Rozansky1, Aditi Bhargava1, Meredith Leong2, Gary L. Firestone2, and David Pearce1

1 Division of Nephrology, Department of Medicine, and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco 94143; and 2 Department of Molecular and Cell Biology, University of California, Berkeley, California 94720

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.

epithelial sodium channel; phosphatidylinositol 3-kinase; serine-threonine kinase

* J. Wang and P. Barbry contributed equally to this work.




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