|Budget Amount *help
¥3,500,000 (Direct Cost : ¥3,500,000)
Fiscal Year 2003 : ¥1,200,000 (Direct Cost : ¥1,200,000)
Fiscal Year 2002 : ¥2,300,000 (Direct Cost : ¥2,300,000)
The present study was conducted to elucidate the mechanism of chronic cyclosporine nephrotoxicity. We utilized cDNA microarray (Atras Rat 1.2 array, Atras 1.2 Array2, Clontech) and examined expression of 2,352 genes from rat kidneys suffering chronic nephrotoxicity with another calcineurin inhibitor, tacrolimus. We found enhanced gene expression of hundreds of gene in the kidney of chronic nephrotoxicity. Those included E-selectin, VCAM-1, fas antigen ligand, fas antigen, IL-6,G-CSF and u-PA which were known to be regulated by a transcription factor, nuclear factor kappaB (NF-kB). Electrophoretic mobility shift assay of nuclear protein from diseased kidney showed that DNA binding activity of not only NF-kB but also AP-1 were markedly enhanced in the kidney treated with either cyclosporine or tacrolimus. These changes were almost abolished when rats were simultaneously maintained on high magnesium diet or putative NF-kB inhibitor, PDTC. Renal interstitial fibrosis seen in chronic nephrotoxicity was also attenuated by these treatments.These results suggested that NF-kB play an important role in the pathogenesis of chronic nephrotoxicity of calcineurin inhibitors. Furthermore, Mg supplementation attenuated chronic nephrotoxocity possibly via inhibition of NF-kB activation. To further demonstrate the role of NF-kB in the pathogenesis of renal ineterstitial fibrosis, we utilized rat model of renal fibrosis, obstructive nephropathy. Either PDTC or a proteasome inhibitor that inhibits NF-kB activation through different mode of mechanism significantly attenuated renal fibrosis. Further, oral adsorbent, AST-120 markedly attenuated NF-kB activation and development of renal fibrosis observed in remnant kidney. Thus, our study suggested that NF-kB activation is one of possible targets in treating renal fibrosis that is a main determinant of progressive renal disease.