Activation of transcription factor NF-kappa B in experimental glomerulonephritis in rats.
NF-kappa B plays a pivotal role in cells of the immune system as an inducible transcriptional activator. NF-kappa B 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-kappa B DNA-binding activity in glomeruli of WKY rats injected with nephrotoxic serum (NTS). Kinetic analysis indicated that the NF-kappa B 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-kappa B activation persisted at least until day 14. Pyrrolidine dithiocarbamate (PDTC), a potent inhibitor of NF-kappa B activation, inhibited the NTS-induced increase of glomerular NF-kappa B DNA-binding activity, followed by the inhibition of mRNA expression of IL-1 beta, MCP-1, ICAM-1 and iNOS, which are known to be regulated by NF-kappa B. PDTC also prevented urinary protein excretion which is a pathophysiological parameter for glomerulonephritis. These results suggest that NF-kappa B activation causes the induction of pro-inflammatory factors in nephritic glomeruli, which may play significant roles in the pathogenesis of glomerulonephritis.
Sakurai
H
H
Lead Generation Research Laboratory, Tanabe Seiyaku Co., Ltd., Osaka, Japan.
Hisada
Y
Y
Ueno
M
M
Sugiura
M
M
Kawashima
K
K
Sugita
T
T
D000818:Animals; D001483:Base Sequence; D004268:DNA-Binding Proteins / Q000378:metabolism; D015870:Gene Expression; D005921:Glomerulonephritis / Q000378:metabolism*; D008297:Male; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D009841:Oligonucleotides / Q000737:chemistry; D011507:Proteinuria / Q000139:chemically induced; D011759:Pyrrolidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011921:Rats, Inbred WKY; D017382:Reactive Oxygen Species / Q000378:metabolism; D013859:Thiocarbamates / Q000494:pharmacology
D004268:DNA-Binding Proteins; D016328:NF-kappa B; D009841:Oligonucleotides; D011759:Pyrrolidines; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D013859:Thiocarbamates; C020972:pyrrolidine dithiocarbamic acid; D019001:Nitric Oxide Synthase