| Budget Amount *help |
¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000)
Fiscal Year 2011: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2010: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
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| Research Abstract |
Nilotinib is a second-generation tyrosine kinase inhibitor that demonstrates a 30-fold increase in activity against Bcr-Abl, and a similar level of activity against the PDGF receptor(PDGFR) and c-Kit when compared to imatinib, a compound that has been previously shown to exhibit therapeutic benefits in animal models of renal disease, including cryoglobulinemic membranoproliferative glomerulonephritis and nephrotoxic serum nephritis. In the current study, we investigated the role of nilotinib in the progression of established renal failure. Adult male Sprague Dawley rats were subjected to 5/6 nephrectomy or laparotomy(sham-operated). Rats with 5/6 nephrectomy were then administered either nilotinib(45mg/kg) or vehicle via daily oral gavage from 2 weeks after surgery, and for a period of 8 weeks. Blood pressure(BP), proteinuria(U-P), serum creatinine(Cr) and body weight(BW) were measured periodically. Renal morphological investigations were performed at sacrifice. In vitro, we used renal
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fibroblasts(NRK49F) and primary mesangial cells. Cells were pretreated with nilotinib or medium alone, and collagen type I synthesis and PDGFR. phosphorylation induced by angiotensin II or PDGF-BB were analyzed by real-time RT-PCR and immunoblotting. BP and BW were comparable between the two treatment groups throughout the study. Following 6 and 8 weeks of treatment, serum Cr levels in the nilotinib-treated rats were significantly lower than that of the vehicle-treated rats. When compared to vehicle treatment, nilotinib-treated rats demonstrated reduced U-P at 1 week after treatment. This reduction was maintained over the course of the study. Nilotinib treatment also resulted in a decrease in remnant kidney hypertrophy, in addition to reduced scores of glomerulosclerosis and tubulointerstitial damage. Renal cortical mRNA for collagen type I, TGF-β, fibronectin, and PAI-1 were also significantly decreased in the nilotinib treated group. In vitro, nilotinib blocked collagen type I/GAPDH mRNA production induced by angiotensin-II in renal fibroblasts and mesangial cells. Nilotinib also decreased collagen type I/GAPDH mRNA levels and prevented PDGFR. phosphorylation induced by PDGF-BB in mesangial cells. Nilotinib treatment significantly attenuates renal fibrosis in vivo and in vitro. Our results suggest that nilotinib may prove useful in limiting the progression of chronic renal disease to end-stage renal failure. Less
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