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Sci. Signal., 18 May 2010
Vol. 3, Issue 122, p. ra39
[DOI: 10.1126/scisignal.2000678]

RESEARCH ARTICLES

c-mip Impairs Podocyte Proximal Signaling and Induces Heavy Proteinuria

Shao-yu Zhang1,2, Maud Kamal1,2*, Karine Dahan1,2*, André Pawlak1,2*, Virginie Ory1,2, Dominique Desvaux1,2, Vincent Audard1,2, Marina Candelier1,2, Fatima BenMohamed1,2, Marie Matignon1,2, Christo Christov3,4, Xavier Decrouy4, Veronique Bernard5, Gilles Mangiapan6, Philippe Lang1,2,7,8, Georges Guellaën1,2, Pierre Ronco9,10,11, and Djillali Sahali1,2,7,8{dagger}

1 INSERM, UMR 955, Equipe 21, F-94010 Créteil, France.
2 UMRS 955, Equipe 21, Université Paris-Est Créteil Val-de-Marne, F-94010 Créteil, France.
3 Assistance publique-Hôpitaux de Paris (AP-HP), Groupe hospitalier Henri Mondor-Albert Chenevier, Service d’histologie, Département de Pathologie, F-94010 Créteil, France.
4 INSERM, UMR 955, Plate-Forme d’Imagerie Cellulaire et Tissulaire, F-94010 Créteil, France.
5 Unité INSERM, UMR 952, CNRS UMR7224, Université Pierre et Marie Curie, F-75252 Paris, France.
6 Centre hospitalier intercommunal, Service de pneumologie, F-94010 Créteil, France.
7 AP-HP, Groupe hospitalier Henri Mondor–Albert Chenevier, Service de Néphrologie, F-94010 Créteil, France.
8 Institut francilien de recherche en néphrologie et transplantation Henri Mondor, F-94010 Créteil, France.
9 INSERM, UMRS-702, F-75020 Paris, France.
10 Université Pierre et Marie Curie–Paris 6, 75252 Paris Cedex 05, France.
11 AP-HP, Hôpital Tenon, Service de Néphrologie et Dialyses, F-75020 Paris, France.

* These authors contributed equally to this work.

Abstract: Idiopathic nephrotic syndrome comprises several podocyte diseases of unknown origin that affect the glomerular podocyte, which controls the permeability of the filtration barrier in the kidney to proteins. It is characterized by the daily loss of more than 3 g of protein in urine and the lack of inflammatory lesions or cell infiltration. We found that the abundance of c-mip (c-maf inducing protein) was increased in the podocytes of patients with various acquired idiopathic nephrotic syndromes in which the podocyte is the main target of injury. Mice engineered to have excessive c-mip in podocytes developed proteinuria without morphological alterations, inflammatory lesions, or cell infiltration. Excessive c-mip blocked podocyte signaling by preventing the interaction of the slit diaphragm transmembrane protein nephrin with the tyrosine kinase Fyn, thereby decreasing phosphorylation of nephrin in vitro and in vivo. Moreover, c-mip inhibited interactions between Fyn and the cytoskeletal regulator N-WASP (neural Wiskott-Aldrich syndrome protein) and between the adaptor protein Nck and nephrin, potentially accounting for cytoskeletal disorganization and the effacement of foot processes seen in idiopathic nephrotic syndromes. The intravenous injection of small interfering RNA targeting c-mip prevented lipopolysaccharide-induced proteinuria in mice. Together, these results identify c-mip as a key component in the molecular pathogenesis of acquired podocyte diseases.

{dagger} To whom correspondence should be addressed. E-mail: dil.sahali{at}inserm.fr

Citation: S. y. Zhang, M. Kamal, K. Dahan, A. Pawlak, V. Ory, D. Desvaux, V. Audard, M. Candelier, F. BenMohamed, M. Matignon, C. Christov, X. Decrouy, V. Bernard, G. Mangiapan, P. Lang, G. Guellaën, P. Ronco, D. Sahali, c-mip Impairs Podocyte Proximal Signaling and Induces Heavy Proteinuria. Sci. Signal. 3, ra39 (2010).

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