Nephrin Deficiency Activates NF-κB and Promotes Glomerular Injury

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