Activation of transcription factor NF-κB in experimental glomerulonephritis in rats

NF-κB plays a pivotal role in cells of the immune system as an inducible transcriptional activator. NF-κB regulates the transcription of many genes of pro-inflammatory cytokines and cell adhesion molecules, which could be involved in the pathogenesis of glomerulonephritis. Using a gel shift assay, we investigated NF-κB DNA-binding activity-in glomeruli of WKY rats injected with nephrotoxic serum (NTS). Kinetic analysis indicated that the NF-κB DNA-binding activity in glomeruli, composed of p50 subunit determined by a supershift assay, increased on day 1 after NTS injection and the maximal activation was observed on day 3 to 5. NF-κB activation persisted at least until day 14. Pyrrolidine dithiocarbamate (PDTC), a potent inhibitor of NF-κB activation, inhibited the NTS-induced increase of glomerular NF-κB DNA-binding activity, followed by the inhibition of mRNA expression of IL-1β, MCP-1, ICAM-1 and iNOS, which are known to be regulated by NF-κB. PDTC also prevented urinary protein excretion which is a pathophysiological parameter for glomerulonephritis. These results suggest that NF-κB activation causes the induction of pro-inflammatory factors in nephritic glomeruli, which may play significant roles in the pathogenesis of glomerulonephritis.