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J. Biol. Chem., Vol. 283, Issue 37, 25671-25681, September 12, 2008

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NF-B Inhibits Sodium Transport via Down-regulation of SGK1 in Renal Collecting Duct Principal Cells^*

Sophie de Seigneux, Valérie Leroy, Hafida Ghzili, Martine Rousselot, Søren Nielsen, Bernard C. Rossier^¶, Pierre-Yves Martin, and Eric Féraille¹

From the Service de Néphrologie, Fondation pour Recherches Médicales, 1211 Genève 4, Switzerland, ^¶Department of Pharmacology and Toxicology, University of Lausanne, 1005 Lausanne, Switzerland, and The Water and Salt Research Center, Institute of Anatomy, University of Aarhus, 8000 Aarhus, Denmark

Tubulointerstitial inflammation is a common feature of renal diseases. We have investigated the relationship between inflammation and Na⁺ transport in the collecting duct (CD) using the mCCD_cl1 and mpkCDD_cl4 principal cell models. Lipopolysaccharide (LPS) decreased basal and aldosterone-stimulated amiloride-sensitive transepithelial current in a time-dependent manner. This effect was associated with a decrease in serum and gucocorticoid-regulated kinase 1 (SGK1) mRNA and protein levels followed by a decrease in epithelial sodium channel (ENaC) -subunit mRNA levels. The LPS-induced decrease in SGK1 expression was confirmed in isolated rat CD. This decreased expression of either SGK1 or the ENaC -subunit was not due to enhanced degradation of mRNA. In contrast, LPS inhibited transcriptional activity of the SGK1 promoter measured by luciferase-reporter gene assay. The effect of LPS was not mediated by inhibition of mineralocorticoid or glucocorticoid receptor, because expression of both receptors was unchanged and blockade of either receptor by spironolactone or RU486, respectively, did not prevent the down-regulation of SGK1. The effect of LPS was mediated by the canonical NF-B pathway, as overexpression of a constitutively active mutant, IKKβ (inhibitor of nuclear factor B kinase-β) decreased SGK1 mRNA levels, and knockdown of p65 NF-B subunit by small interfering RNA increased SGK1 mRNA levels. Chromatin immunoprecipitation showed that LPS increased p65 binding to two NF-B sites along the SGK1 promoter. In conclusion, we show that activation of the NF-B pathway down-regulates SGK1 expression, which might lead to decreased ENaC -subunit expression, ultimately resulting in decreased Na⁺ transport.

Received for publication, May 19, 2008 , and in revised form, June 17, 2008.

^* This work was supported by Swiss National Foundation Grant 31-109473 and by grants from the Novartis Foundation (to E. F.), the Ernest Boninchi Foundation, the Société Académique de Genève, and the Ernst and Lucie Schmidheiny Foundation (to S. d. S.). 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 To whom correspondence should be addressed: Service de Néphrologie, Fondation pour Recherches Médicales, 64 Ave. de la Roseraie, CH-1211, Genève 4, Switzerland. Tel.: 41-22-382-38-37; Fax: 41-22-347-59-79; E-mail: Eric.Feraille{at}medecine.unige.ch.

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