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J. Biol. Chem., Vol. 283, Issue 39, 26643-26661, September 26, 2008

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Acute Hypertonicity Alters Aquaporin-2 Trafficking and Induces a MAPK-dependent Accumulation at the Plasma Membrane of Renal Epithelial Cells^*

From the Massachusetts General Hospital Center for Systems Biology, Program in Membrane Biology and Nephrology Division, Massachusetts General Hospital and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02114-2790

The unique phenotype of renal medullary cells allows them to survive and functionally adapt to changes of interstitial osmolality/tonicity. We investigated the effects of acute hypertonic challenge on AQP2 (aquaporin-2) water channel trafficking. In the absence of vasopressin, hypertonicity alone induced rapid (<10 min) plasma membrane accumulation of AQP2 in rat kidney collecting duct principal cells in situ, and in several kidney epithelial lines. Confocal microscopy revealed that AQP2 also accumulated in the trans-Golgi network (TGN) following hypertonic challenge. AQP2 mutants that mimic the Ser²⁵⁶-phosphorylated and -nonphosphorylated state accumulated at the cell surface and TGN, respectively. Hypertonicity did not induce a change in cytosolic cAMP concentration, but inhibition of either calmodulin or cAMP-dependent protein kinase A activity blunted the hypertonicity-induced increase of AQP2 cell surface expression. Hypertonicity increased p38, ERK1/2, and JNK MAPK activity. Inhibiting MAPK activity abolished hypertonicity-induced accumulation of AQP2 at the cell surface but did not affect either vasopressin-dependent AQP2 trafficking or hypertonicity-induced AQP2 accumulation in the TGN. Finally, increased AQP2 cell surface expression induced by hypertonicity largely resulted from a reduction in endocytosis but not from an increase in exocytosis. These data indicate that acute hypertonicity profoundly alters AQP2 trafficking and that hypertonicity-induced AQP2 accumulation at the cell surface depends on MAP kinase activity. This may have important implications on adaptational processes governing transcellular water flux and/or cell survival under extreme conditions of hypertonicity.

Received for publication, February 8, 2008 , and in revised form, June 10, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant DK38452 (to D. B.). The Microscopy Core facility of the Massachusetts General Hospital Program in Membrane Biology receives additional support from the Boston Area Diabetes and Endocrinology Research Center (DK57521) and the Center for the Study of Inflammatory Bowel Disease (DK43341). 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.

² Supported by a doctoral level postgraduate scholarship from Natural Sciences and Engineering Council of Canada.

³ Recipient of a Young Investigator Award from the National Kidney Foundation.

⁴ Supported by National Institutes of Health KO8 Grant DK075940-01.

¹ To whom correspondence should be addressed: Service de Néphrologie, Fondation pour Recherches Médicales, 64 Avenue de la Roseraie, CH-1211, Geneva 4, Switzerland. Tel.: 617-726-7496; Fax: 617-643-3182; E-mail: Udo.Hasler{at}medecine.unige.ch.

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