HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

Am J Physiol Renal Physiol 292: F577-F585, 2007. First published October 3, 2006; doi:10.1152/ajprenal.00240.2006
0363-6127/07 $8.00

This Article Free upon publication Full Text Full Text (PDF) All Versions of this Article: 292/2/F577    most recent 00240.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by Fuster, D. G. Articles by Moe, O. W. Search for Related Content PubMed PubMed Citation Articles by Fuster, D. G. Articles by Moe, O. W.

Characterization of the regulation of renal Na⁺/H⁺ exchanger NHE3 by insulin

¹Department of Internal Medicine and ²Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas; and ³Department of Physiology, University of Maryland, Baltimore, Maryland

Submitted 27 June 2006 ; accepted in final form 26 September 2006

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 paper characterizes the signaling pathway by which insulin stimulates NHE3 in a cell culture model [opossum kidney (OK) cell]. Insulin has two distinct phases of action on NHE3. Chronic insulin (24 h) activates NHE3 through the classic phosphatidylinositol 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 cells. We previously showed that glucocorticoids augment the effect of insulin on NHE3 (Klisic J, Hu MC, Nief V, Reyes L, Fuster D, Moe OW, Ambuhl PM. Am J Physiol Renal Physiol 283: F532–F539, 2002). 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 h) 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 1 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.

Na⁺/H⁺ exchanger isoform 3; serum- and glucocorticoid-dependent kinase 1

This article has been cited by other articles:

				D. G. Fuster, J. Zhang, M. Shi, I. A. Bobulescu, S. Andersson, and O. W. Moe Characterization of the Sodium/Hydrogen Exchanger NHA2 J. Am. Soc. Nephrol., August 1, 2008; 19(8): 1547 - 1556. [Abstract] [Full Text] [PDF]

				I. A. Bobulescu, M. Dubree, J. Zhang, P. McLeroy, and O. W. Moe Effect of renal lipid accumulation on proximal tubule Na+/H+ exchange and ammonium secretion Am J Physiol Renal Physiol, June 1, 2008; 294(6): F1315 - F1322. [Abstract] [Full Text] [PDF]

				S. Tiwari, S. Riazi, and C. A. Ecelbarger Insulin's impact on renal sodium transport and blood pressure in health, obesity, and diabetes Am J Physiol Renal Physiol, October 1, 2007; 293(4): F974 - F984. [Abstract] [Full Text] [PDF]

				H. Kiwull-Schone, P. Kiwull, S. Frede, and M. Wiemann Role of Brainstem Sodium/Proton Exchanger 3 for Breathing Control during Chronic Acid Base Imbalance Am. J. Respir. Crit. Care Med., September 1, 2007; 176(5): 513 - 519. [Abstract] [Full Text] [PDF]