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Kidney Int. 2016 Dec;90(6):1298-1311. doi: 10.1016/j.kint.2016.07.016. Epub 2016 Sep 17.

Repression of CMIP transcription by WT1 is relevant to podocyte health.

Author information

1
Institut National de la Santé et de la Recherche Médicale, Créteil, France; Université Paris Est, Faculté de Médecine, Créteil, France.
2
Institut National de la Santé et de la Recherche Médicale, Créteil, France; Université Paris Est, Faculté de Médecine, Créteil, France; AP-HP, Groupe Henri-Mondor Albert-Chenevier, Service de Néphrologie, Créteil, France; Institut Francilien de Recherche en Néphrologie et Transplantation, Henri Mondor Hospital, Créteil, France.
3
Centre Chirurgical Marie Lannelongue, Institut National de la Santé et de la Recherche Médicale, Le Plessis Robinson, France; Faculté de Médecine, Université Paris-Sud, Le Kremlin-Bicêtre, France.
4
University of Otago, Dunedin, New Zealand.
5
Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche, University of Nice/Sophia Antipolis, Nice, France.
6
APHP, Centre de Référence des Maladies Rénales Héréditaires de l'enfant et de l'adulte et Service de Néphrologie Pédiatrique, Hôpital Universitaire Necker-Enfants Malades, Paris, France.
7
Institut National de la Santé et de la Recherche Médicale, Créteil, France; Université Paris Est, Faculté de Médecine, Créteil, France; AP-HP, Groupe Henri-Mondor Albert-Chenevier, Service de Néphrologie, Créteil, France; Institut Francilien de Recherche en Néphrologie et Transplantation, Henri Mondor Hospital, Créteil, France. Electronic address: dil.sahali@inserm.fr.

Abstract

The WT1 (Wilm's tumor suppressor) gene is expressed throughout life in podocytes and is essential for the functional integrity of the glomerular filtration barrier. We have previously shown that CMIP (C-Maf inducing protein) is overproduced in podocyte diseases and alters intracellular signaling. Here we isolated the proximal region of the human CMIP promoter and showed by chromatin immunoprecipitation assays and electrophoretic-mobility shift that Wilm's tumor protein (WT1) bound to 2 WT1 response elements, located at positions -290/-274 and -57/-41 relative to transcription start site. Unlike the human CMIP gene, only one Wt1 response element was identified in the mouse Cmip proximal promoter located at position -217/-206. Luciferase reporter assays indicated that WT1 dose-dependently inhibited the transcriptional induction of the CMIP promoter. Transfection of decoy oligonucleotides mimicking the WT1 response elements prevented the inhibition of WT1 on CMIP promoter activity. Furthermore, WT1 silencing promoted Cmip expression. In line with these findings, the abundance of Cmip was early and significantly increased at the transcript and protein level in podocytes displaying a primary defect in Wt1, including Denys-Drash syndrome and Frasier syndrome. Thus, WT1 is a major repressor of the CMIP gene in physiological situations, while conditional deletion of CMIP in the developing kidney did not affect the development of mature glomeruli.

KEYWORDS:

cell signaling; gene expression; kidney development; nephrotic syndrome; podocyte; transcription regulation

PMID:
27650733
DOI:
10.1016/j.kint.2016.07.016
[Indexed for MEDLINE]

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