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J. Biol. Chem., Vol. 282, Issue 41, 29866-29873, October 12, 2007

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Akt Mediates the Effect of Insulin on Epithelial Sodium Channels by Inhibiting Nedd4-2^*

Il-Ha Lee, Anuwat Dinudom¹, Angeles Sanchez-Perez, Sharad Kumar², and David I. Cook³

From the Discipline of Physiology, School of Medical Science, Faculty of Medicine, University of Sydney, Sydney, New South Wales 2006 and Hanson Centre for Cancer Research, Institute of Medical and Veterinary Science, Frome Road, Adelaide, South Australia 500, Australia

The epithelial sodium channel (ENaC) plays an important role in transepithelial Na⁺ absorption; hence its function is essential for maintaining Na⁺ and fluid homeostasis and regulating blood pressure. Insulin is one of the hormones that regulates activity of ENaC. In this study, we investigated the contribution of two related protein kinases, Akt (also known as protein kinase B) and the serum- and glucocorticoid-dependent kinase (Sgk), on insulin-induced ENaC activity in Fisher rat thyroid cells expressing ENaC. Overexpression of Akt1 or Sgk1 significantly increased ENaC activity, whereas expression of a dominant-negative construct of Akt1, Akt1_K179M, decreased basal activity of ENaC. Inhibition of the endogenous expression of Akt1 and Sgk1 by short interfering RNA not only inhibited ENaC but also disrupted the stimulatory effect on ENaC of insulin and of the downstream effectors of insulin, phosphatidylinositol 3-kinase and PDK1. Conversely, overexpression of Akt1 or Sgk1 increased expression of ENaC at the cell membrane and overcame the inhibitory effect of Nedd4-2 on ENaC. Furthermore, mutation of consensus phosphorylation sites on Nedd4-2 for Akt1 and Sgk1, Ser³⁴² and Ser⁴²⁸, completely abolished the inhibitory effect of Sgk1 and Akt1 on Nedd4-2 action. Together these data suggest that both Akt and Sgk are components of an insulin signaling pathway that increases Na⁺ absorption by up-regulating membrane expression of ENaC via a regulatory system that involves inhibition of Nedd4-2.

Received for publication, March 6, 2007 , and in revised form, August 21, 2007.

^* This work was supported by National Health and Medical Research Council of Australia Grant 349320 and Australian Research Council Grant DP0774320. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ National Health and Medical Research Council Senior Research Fellow.

² National Health and Medical Research Council Senior Principal Research Fellow.

³ To whom correspondence should be addressed: Medical Foundation Bldg., 92-94 Parramatta Rd., Camperdown, Sydney, New South Wales 2050, Australia. Tel.: 61-2-9036-3314; Fax: 61-2-9036-3316; E-mail: davidc{at}physiol.usyd.edu.au.

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