Inhibition of nuclear factor-kappaB activation by pyrrolidine dithiocarbamate prevents chronic FK506 nephropathy.
BACKGROUND
Chronic tacrolimus (FK506) nephrotoxicity is characterized by renal fibrosis with interstitial inflammation. Since nuclear factor-kappaB (NF-kappaB) plays a key role in chronic inflammatory diseases including renal disease, the present study was conducted to elucidate the role of NF-kappaB in the pathogenesis of chronic FK506-induced nephropathy.


METHODS
FK506 (1 mg/kg/day, SC) was administered daily to rats maintained on low sodium diet for 42 days. Some rats were treated with a putative NF-kappaB inhibitor, pyrrolidine dithiocarbamate (PDTC; 100, 200 mg/kg/day, by gavage). The renal function, renal histology, renal NF-kappaB-DNA binding activity and gene expression profile were examined.


RESULTS
FK506 caused a decline in glomerular filtration and induced characteristic renal morphologic changes including arteriolopathy, tubular atrophy and interstitial fibrosis. FK506 markedly activated renal cortical NF-kappaB-DNA binding. PDTC administration inhibited NF-kappaB-DNA binding activity in a dose dependent manner. With higher dose, NF-kappaB-DNA binding activity was decreased to a control level. PDTC had little effect on FK506-induced renal dysfunction. Renal cortical monocyte/macrophage infiltration observed in FK506-treated rats was dramatically suppressed by PDTC. FK506 up-regulated renal cortical gene expression of chemoattractant proteins, monocyte chemoattractant protein-1 (MCP-1) and osteopontin. PDTC significantly blocked MCP-1 gene expression but had no effect on osteopontin gene expression. Tubular atrophy and tubulointerstitial fibrosis, but not arteriolopathy, were significantly attenuated by PDTC. FK506 increased renal mRNA expression of fibrogenic molecules and extracellular matrices that also were attenuated by PDTC treatment.


CONCLUSIONS
NF-kappaB plays an important role in mediating cortical monocyte/macrophage infiltration and in the pathogenesis of tubular injury and interstitial fibrosis in experimental FK506-induced chronic nephropathy.
Tamada
Satoshi
S
Department of Urology, Osaka City University, Osaka, Japan.
Nakatani
Tatsuya
T
Asai
Toshihiro
T
Tashiro
Koichiro
K
Komiya
Toshiyuki
T
Sumi
Tomohiko
T
Okamura
Mikio
M
Kim
Shokei
S
Iwao
Hiroshi
H
Kishimoto
Taketoshi
T
Yamanaka
Shinya
S
Miura
Katsuyuki
K
D000818:Animals; D018932:Chemokine CCL2 / Q000235:genetics; D002908:Chronic Disease; D024202:Electrophoretic Mobility Shift Assay; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000633:toxicity*; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced / Q000188:drug therapy / Q000517:prevention & control*; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D008297:Male; D009000:Monocytes / Q000187:drug effects / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism*; D053495:Osteopontin; D011759:Pyrrolidines / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012795:Sialoglycoproteins / Q000235:genetics; D016559:Tacrolimus / Q000633:toxicity*; D013859:Thiocarbamates / Q000378:metabolism*
D018932:Chemokine CCL2; D007166:Immunosuppressive Agents; D016328:NF-kappa B; D011759:Pyrrolidines; D012333:RNA, Messenger; D012795:Sialoglycoproteins; C506897:Spp1 protein, rat; D013859:Thiocarbamates; D053495:Osteopontin; C020972:pyrrolidine dithiocarbamic acid; D016559:Tacrolimus