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J Am Soc Nephrol. 2009 Aug;20(8):1733-43. doi: 10.1681/ASN.2008111219. Epub 2009 Jun 4.

Nephrin deficiency activates NF-kappaB and promotes glomerular injury.

Author information

1
Molecular Medicine Unit, Institute of Child Health, London, UK. a.koziell@ich.ucl.ac.uk

Abstract

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

PMID:
19497968
PMCID:
PMC2723981
DOI:
10.1681/ASN.2008111219
[Indexed for MEDLINE]
Free PMC Article

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