期刊
AMERICAN JOURNAL OF TRANSPLANTATION
卷 2, 期 2, 页码 111-119出版社
WILEY
DOI: 10.1034/j.1600-6143.2002.020201.x
关键词
biglycan; chronic nephrotoxicity; cyclosporine; extracellular matrix; fibrosis; pirfenidone; plasminogen activator inhibitor-1; rats; transforming growth factor-beta 1
Chronic cyclosporine (CsA) nephrotoxicity is characterised by tubulointerstitial fibrosis. Pirfenidone (PFD) is a novel antifibrotic compound that was shown to prevent and even reverse fibrosis. The mechanism of action of PFD is unclear but involves inhibition of transforming growth factor-beta (TGF-beta). Salt-depleted rats were administered CsA, CsA+PFD, vehicle (VH) or VH+PFD and sacrificed at 28days. Physiologic and histologic changes were studied in addition to TGF-beta1, plasminogen activator inhibitor-1 (PAl-1) and biglycan mRNA expressions by Northern blot. TGF-beta1 immunohistochemistry was also performed. Treatment with PFD ameliorated CsA-induced fibrosis by about 50% (p <0.05). CsA-induced decrease in creatinine clearance improved with PFD but the difference was not significant. TGF-beta1, PAl-1 and biglycan mRNA expressions increased with CsA (p <0.05 vs. VH) but strikingly improved with PFD treatment (p <0.05 vs. CsA), which brought the levels down to VH levels. PFD treatment also decreased TGF-beta1 protein expression by 80%. These results demonstrate that PFD can attenuate renal fibrosis in this model. PFD was associated with a decrease in TGF-beta1 expression, which, in turn, was associated with a decrease in matrix deposition. These experiments suggest that PFD can be clinically useful for preventing chronic CsA nephrotoxicity and may prove to be helpful in other progressive renal diseases.
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