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The Major Podocyte Protein Nephrin Is Transcriptionally Activated by the Wilms’ Tumor Suppressor WT1

Nicole Wagner^*, Kay-Dietrich Wagner^*, Yiming Xing, Holger Scholz and Andreas Schedl^*

*INSERM U636, Centre de Biochimie, Faculté des Sciences, Nice, France; Department of Development & Cell Biology, UCI, Irvine California; and Institut für Physiologie, Charité, Universitätsmedizin Berlin, Berlin, Germany

Correspondence to Dr. Andreas Schedl, INSERM U636, Centre de Biochimie, Parc Valrose, 06108 Nice, France. Phone: +33-04-92-07-6401; Fax: +33-04-92-07-6475; E-mail: schedl{at}unice.fr

NPHS1 encodes the structural protein nephrin, which has a crucial role in the filtration barrier of the glomerular podocyte. Mutations or deregulation of NPHS1 are associated with a variety of renal diseases, including the Finnish type congenital nephrotic syndrome. This study analyzed a potential regulation of nephrin by the Wilms’ tumor protein, Wt1. Using an inducible U2OS osteosarcoma cell line, it is shown that upon Wt1 induction, endogenous nephrin mRNA becomes highly upregulated. Co-transfection studies demonstrate that Wt1 can activate the nephrin promoter >10-fold. DNase footprinting and mutation analysis identify a Wt1 responsive element in the nephrin promoter, which is required for the binding of Wt1 protein. Mutations or deletion of this Wt1 responsive element completely abolished transactivation of the nephrin promoter by Wt1. Moreover, transgenic analysis demonstrates the requirement of the identified binding site to direct podocyte-specific expression of a reporter gene in transgenic mice, thus confirming the importance of this site for the regulation of nephrin in vivo. Finally, it is shown that nephrin expression is lowest in kidneys of mice that lack specifically the Wt1(–KTS) splice variant, but in comparison with wild-type littermates, it is also reduced in animals with disruption of the Wt1(+KTS) splice variant. Taken together, these data identify nephrin as a direct transcriptional target for Wt1 and underline the importance of Wt1 as a key regulator in podocyte function.

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