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This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: ASN.2007070781v1 19/10/1965    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Van Huyen, J. P. D. Articles by Doucet, A. PubMed PubMed Citation Articles by Van Huyen, J. P. D. Articles by Doucet, A.

GDF15 Triggers Homeostatic Proliferation of Acid-Secreting Collecting Duct Cells

Jean Paul Duong Van Huyen^*, Lydie Cheval, May Bloch-Faure, Marie France Belair^*, Didier Heudes^*, Patrick Bruneval^* and Alain Doucet

^* UPMC University of Paris 06, Unité Mixte de Recherche Scientifique (UMRS) 872, and INSERM, UMRS 872, and UPMC University of Paris 06, Unité Mixte de Recherche (UMR) 7134, Laboratoire de physiologie et génomique rénales, and CNRS, UMR 7134, Laboratoire de physiologie et génomique rénales, Paris, France

Correspondence: Dr. Alain Doucet, UMR 7134, Institut des Cordeliers, 15 rue de l'Ecole de Médecine, 75270 Paris cedex 6, France. Phone: 33-1-55-42-78-51; Fax: 33-1-46-33-41-72; E-mail: alain.doucet{at}bhdc.jussieu.fr

Received for publication July 19, 2007. Accepted for publication May 26, 2008.

Although adult kidney cells are quiescent, enlargement of specific populations of epithelial cells occurs during repair and adaptive processes. A prerequisite to the development of regenerative therapeutics is to identify the mechanisms and factors that control the size of specific populations of renal cells. Unfortunately, in most cases, it is unknown whether the growth of cell populations results from transdifferentiation or proliferation and whether proliferating cells derive from epithelial cells or from circulating or resident progenitors. In this study, the mechanisms underlying the enlargement of the acid-secreting cell population in the mouse kidney collecting duct in response to metabolic acidosis was investigated. Acidosis led to two phases of proliferation that preferentially affected the acid-secreting cells of the outer medullary collecting duct. All proliferating cells displayed polarized expression of functional markers. The first phase of proliferation, which started within 24 h and peaked at day 3, was dependent on the overexpression of growth differentiation factor 15 (GDF15) and cyclin D1 and was abolished when phosphatidylinositol-3 kinase and mammalian target of rapamycin were inhibited. During this phase, cells mostly divided along the tubular axis, contributing to tubule lengthening. The second phase of proliferation was independent of GDF15 but was associated with induction of cyclin D3. During this phase, cells divided transversely. In summary, acid-secreting cells proliferate as the collecting duct adapts to metabolic acidosis, and GDF15 seems to be an important determinant of collecting duct lengthening.

Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673