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J. Biol. Chem., Vol. 283, Issue 5, 2622-2630, February 1, 2008

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Postnatal Requirement of the Epithelial Sodium Channel for Maintenance of Epidermal Barrier Function^*

Roch-Philippe Charles, Marjorie Guitard¹, Céline Leyvraz, Bernadette Breiden, Marek Haftek^¶, Zofia Haftek-Terreau^¶, Jean-Christophe Stehle^||, Konrad Sandhoff, and Edith Hummler²

From the Département de Pharmacologie & de Toxicologie, Université de Lausanne, CH-1005 Lausanne, Switzerland, the ^||Département de Pathologie, Université de Lausanne, CH-1005 Lausanne, Switzerland, LIMES, Membrane Biology and Lipid Biochemistry Unit, c/o, Kekulé-Institut für Organische Chemie und Biochemie der Universität Bonn, D-53121 Bonn, Germany, and the ^¶Laboratoire Joliot-Curie, IFR128, Ecole Normale Supérieure de Lyon, T-69000 Lyon, France

In skin, the physiological consequence of an epithelial sodium channel (ENaC) deficiency is not obvious directly at birth. Nevertheless, within hours after birth, mice deficient for the -subunit of the highly amiloride-sensitive epithelial sodium channel (ENaC/Scnn1a) suffer from a significant increased dehydration. This is characterized by a loss of body weight (by 6% in 6 h) and an increased transepidermal water loss, which is accompanied by a higher skin surface pH in 1-day-old pups. Although early and late differentiation markers, as well as tight junction protein distribution and function, seem unaffected, deficiency of ENaC severely disturbs the stratum corneum lipid composition with decreased ceramide and cholesterol levels, and increased pro-barrier lipids, whereas covalently bound lipids are drastically reduced. Ultrastructural analysis revealed morphological changes in the formation of intercellular lamellar lipids and the lamellar body secretion. Extracellular formation of the lamellar lipids proved to be abnormal in the knockouts. In conclusion, ENaC deficiency results in progressive dehydration and, consequently, weight loss due to severe impairment of lipid formation and secretion. Our data demonstrate that ENaC expression is required for the postnatal maintenance of the epidermal barrier function but not for its generation.

Received for publication, October 25, 2007 , and in revised form, November 16, 2007.

^* This work was supported by the Swiss National Science Foundation (Grants 3100A0-102125/1 and 3100A0-113422/1 to E. H.) and the Deutsche Forschungsgemeinschaft (Grant SFB 645 to B. B. and K. S.). The electron microscopy samples were observed at the Centre Technique des Microscopies, University Lyon 1 by M. Haftek. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S3.

¹ Current address: Cutaneous Biology Research Center, Charlestown, MA 02129.

² To whom correspondence should be addressed: Dr. Edith Hummler, Département de Pharmacologie & de Toxicologie, Université de Lausanne, Rue du Bugnon 27, CH-1005 Lausanne, Switzerland. Tel.: 41-21-692-5357; Fax: 41-21-692-5355; E-mail: Edith.Hummler{at}unil.ch.

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