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1 Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, United States
2 Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, United States; Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas, United States
3 Physiology, University of Maryland, Baltimore, Maryland, United States
* To whom correspondence should be addressed. E-mail: orson.moe{at}utsouthwestern.edu.
Insulin receptors are widely distributed in the kidney and affect multiple aspects of renal function. In the proximal tubule, insulin regulates volume and acid-base regulation through stimulation of the Na+/H+ exchanger NHE3. This manuscript characterizes the signaling pathway by which insulin stimulates NHE3 in a cell culture model (opossum kidney cell; OK cell). Insulin has two distinct phases of action on NHE3. Chronic insulin (24 hr) activates NHE3 through the classical phosphinositol-3-kinase; serum-and glucocorticoid dependent kinase 1 (PI3K/SGK1) pathway as insulin stimulates SGK1 phosphorylation and the insulin effect can be blocked by the PI3K inhibitor wortmannin or a dominant-negative SGK1. We showed that sgk1 transcript and protein are expressed in rat proximal tubule and OK cell. We previously showed that glucocorticoids augment the effect of insulin on NHE3. Part of this can be mediated via induction of SGK1 by glucocorticoids and indeed the insulin effect on NHE3 can also be amplified by overexpression of SGK1. We next addressed the acute effect of insulin (1-2 hr) on NHE3 by systematically examining the candidate signaling cascades and activation mechanisms of NHE3. We ruled out the PI3K-SGK1-Akt and TC10 pathways, increased surface NHE3, NHE3 phosphorylation, NHE3 association with calcineurin homologous protein (CHP1) or megalin as mechanisms of acute activation of NHE3 by insulin. In summary, insulin stimulates NHE3 acutely via yet undefined pathways and mechanisms. The chronic effect of insulin is mediated by the classic PI3K-SGK1 route.
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