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Aldosterone-Induced Serum and Glucocorticoid-Induced Kinase 1 Expression Is Accompanied by Nedd4-2 Phosphorylation and Increased Na⁺ Transport in Cortical Collecting Duct Cells

Sandra Y. Flores^*, Dominique Loffing-Cueni^*, Elena Kamynina^*, Dorothée Daidié^*, Carole Gerbex^*, Sting Chabanel^*, Jean Dudler, Johannes Loffing^*, and Olivier Staub^*

Departments of ^* Pharmacology and Toxicology and Rheumatology, CHUV, University of Lausanne, Lausanne, and Department of Medicine, Unit of Anatomy, University of Fribourg, Fribourg, Switzerland

Address correspondence to: Prof. Olivier Staub, Department of Pharmacology and Toxicology, University of Lausanne, Rue du Bugnon 27, CH-1005 Lausanne, Switzerland. Phone: +41-21-692-5407; Fax: +41-21-692-5355; E-mail: olivier.staub{at}unil.ch

Received for publication October 7, 2004. Accepted for publication May 4, 2005.

Aldosterone plays a central role in Na⁺ homeostasis by controlling Na⁺ reabsorption in the aldosterone-sensitive distal nephron involving the epithelial Na⁺ channel (ENaC). Part of the effects of aldosterone is mediated by serum and glucocorticoid-induced kinase 1 (Sgk1), a Ser/Thr kinase whose expression is rapidly induced by aldosterone and that increases in heterologous expression systems ENaC cell surface abundance and activity. Previous work in Xenopus laevis oocytes suggested that Sgk1 phosphorylates specific residues (Ser212 and Ser328) on the ubiquitin-protein ligase Nedd4-2, an enzyme that directly interacts with ENaC and negatively controls channel density at the plasma membrane. It further indicated that phosphorylation of Nedd4-2 led to impairment of ENaC/Nedd4-2 interaction and consequently to more channels at the cell surface. These data suggested a novel mode of aldosterone-dependent action, yet this was not demonstrated formally in epithelial cells that physiologically express ENaC. Here it is shown, with the use of an anti–phospho-Ser328-mNedd4-2 antibody, that 2 to 6 h of aldosterone treatment induces an increase in Nedd4-2 phosphorylation, both in a mouse cortical collecting duct cell line (mpkCCD_cl4) and in kidneys of adrenalectomized rats. This augmentation, which is accompanied by a raise in Sgk1 expression and transepithelial Na⁺ transport, is sensitive to phosphatidylinositol-3 kinase inhibition, as is Sgk1 phosphorylation and Na⁺ transport. Hence, these data provide evidence in cortical collecting duct cells in vitro and in vivo that Sgk1-dependent phosphorylation of Nedd4-2 is part of the aldosterone response.

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