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Early Aldosterone-Induced Gene Product Regulates the Epithelial Sodium Channel by Deubiquitylation

Panagiotis Fakitsas^*, Gabriele Adam^*, Dorothée Daidié, Miguel X. van Bemmelen, Fatemeh Fouladkou, Andrea Patrignani, Ulrich Wagner, Richard Warth^*, Simone M.R. Camargo^*, Olivier Staub and François Verrey^*

^* Institute of Physiology and Centre for Integrative Human Physiology, University of Zurich, Functional Genomics Centre, Eidgenössische Technische Hochschule & University of Zurich, Zurich, and Institute of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland

Address correspondence to: Dr. François Verrey, Institute of Physiology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland. Phone: +41-44-635-5044/46; Fax: +41-44-635-6814; E-mail: verrey{at}access.unizh.ch

Received for publication August 25, 2006. Accepted for publication January 22, 2007.

The mineralocorticoid hormone aldosterone controls sodium reabsorption and BP largely by regulating the cell-surface expression and function of the epithelial sodium channel (ENaC) in target kidney tubules. Part of the stimulatory effect of aldosterone on ENaC is mediated by the induction of serum- and glucocorticoid-regulated kinase 1 (Sgk1), a kinase that interferes with the ubiquitylation of ENaC by ubiquitin-protein ligase Nedd4-2. In vivo early aldosterone-regulated mRNA now has been identified in microselected mouse distal nephron by microarray. From 22 mRNA that displayed a two-fold or more change, 13 were downregulated and nine were upregulated. Besides Sgk1, the induced mRNA include Grem2 (protein related to DAN and cerebrus [PRDC]), activating transcription factor 3, cAMP responsive element modulator, and the ubiquitin-specific protease Usp2-45. The induction of this last enzyme isoform was verified in mouse distal nephron tubule at the protein level. With the use of Hek293 cells, Xenopus oocytes, and mpkCCD_c14 cells as expression systems, it was shown that Usp2-45 deubiquitylates ENaC and stimulates ENaC-mediated sodium transport, an effect that is not additive to that of Sgk1. A deubiquitylating enzyme that targets ENaC in vitro and thus may play a role in sodium transport regulation was identified within a series of new in vivo early aldosterone-regulated gene products.

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