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Nephrin Deficiency Activates NF-B and Promotes Glomerular Injury

Sagair Hussain^*, Leile Romio^*, Moin Saleem, Peter Mathieson, Manuel Serrano, Jorge Moscat, Maria Diaz-Meco, Peter Scambler^* and Ania Koziell^*

*Molecular Medicine Unit, Institute of Child Health, London, and
Academic Renal Unit, University of Bristol, Southmead Hospital, Bristol, United Kingdom;
Spanish National Cancer Research Centre, Madrid, Spain; and
Department of Genome Science, Genome Research Institute, University of Cincinnati, Cincinnati, Ohio

Correspondence: Dr. Ania Koziell, Molecular Medicine Unit, Institute of Child Health, 30 Guilford St, London, WC1N 1EH, UK. Phone: 00-44-207-242-9789, ext. 0713, 00-44-783-481-4994; Fax: 00-44-207-905-2609; E-mail: a.koziell{at}ich.ucl.ac.uk

Received for publication November 30, 2008. Accepted for publication March 17, 2009.

Increasing evidence implicates activation of NF-B in a variety of glomerular diseases, but the mechanisms involved are unknown. Here, upregulation of NF-B in the podocytes of transgenic mice resulted in glomerulosclerosis and proteinuria. Absence of the podocyte protein nephrin resulted in NF-B activation, suggesting that nephrin negatively regulates the NF-B pathway. Signal transduction assays supported a functional relationship between nephrin and NF-B and suggested the involvement of atypical protein kinase C (aPKC//) as an intermediary. We propose that disruption of the slit diaphragm leads to activation of NF-B; subsequent upregulation of NF-B-driven genes results in glomerular damage mediated by NF-B-dependent pathways. In summary, nephrin may normally limit NF-B activity in the podocyte, suggesting a mechanism by which it might discourage the evolution of glomerular disease.

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Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673