Title | Nephrin deficiency activates NF-kappaB and promotes glomerular injury. |
Publication Type | Journal Article |
Year of Publication | 2009 |
Authors | Hussain S, Romio L, Saleem M, Mathieson P, Serrano M, Moscat J, Diaz-Meco M, Scambler P, Koziell A |
Journal | J Am Soc Nephrol |
Volume | 20 |
Issue | 8 |
Pagination | 1733-43 |
Date Published | 2009 Aug |
ISSN | 1533-3450 |
Keywords | Animals, Apoptosis Regulatory Proteins, Cell Line, Cytoplasm, Dogs, Gene Silencing, Glomerulonephritis, Humans, Intracellular Signaling Peptides and Proteins, Membrane Proteins, Mice, Mice, Knockout, NF-kappa B, Podocytes, Protein Kinase C, Proteinuria, Transcription Factor RelA |
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. |
DOI | 10.1681/ASN.2008111219 |
Alternate Journal | J Am Soc Nephrol |
PubMed ID | 19497968 |
Grant List | / WT_ / Wellcome Trust / United Kingdom |
Related Faculty:
Jorge Moscat, Ph.D. Maria Diaz-Meco Conde, Ph.D.