Nephrin deficiency activates NF-kappaB and promotes glomerular injury

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism*
  • Cell Line
  • Cytoplasm / metabolism
  • Dogs
  • Gene Silencing
  • Glomerulonephritis / metabolism*
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • NF-kappa B / metabolism*
  • Podocytes / metabolism*
  • Protein Kinase C / metabolism
  • Proteinuria / metabolism
  • Transcription Factor RelA / metabolism

Substances

  • Apoptosis Regulatory Proteins
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • NF-kappa B
  • NPHS2 protein
  • Rela protein, mouse
  • Transcription Factor RelA
  • nephrin
  • prostate apoptosis response-4 protein
  • PKC-3 protein
  • Protein Kinase C