Nephrin deficiency activates NF-kappaB and promotes glomerular injury.
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.
Hussain
Sagair
S
Molecular Medicine Unit, Institute of Child Health, London, UK. a.koziell@ich.ucl.ac.uk
Romio
Leile
L
Saleem
Moin
M
Mathieson
Peter
P
Serrano
Manuel
M
Moscat
Jorge
J
Diaz-Meco
Maria
M
Scambler
Peter
P
Koziell
Ania
A
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D003593:Cytoplasm / Q000378:metabolism; D004285:Dogs; D020868:Gene Silencing; D005921:Glomerulonephritis / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D050199:Podocytes / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D011507:Proteinuria / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D016328:NF-kappa B; C407223:NPHS2 protein; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; C113267:nephrin; C101296:prostate apoptosis response-4 protein; C115015:PKC-3 protein; D011493:Protein Kinase C