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Pirfenidone Treatment Decreases Transforming Growth Factor‐β1 and Matrix Proteins and Ameliorates Fibrosis in Chronic Cyclosporine Nephrotoxicity
Author(s) -
Shihab Fuad S.,
Bennett William M.,
Yi Hong,
Andoh Takeshi F.
Publication year - 2002
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1034/j.1600-6143.2002.020201.x
Subject(s) - pirfenidone , medicine , nephrotoxicity , transforming growth factor , fibrosis , biglycan , transforming growth factor beta , creatinine , endocrinology , pharmacology , kidney , idiopathic pulmonary fibrosis , decorin , lung , cartilage , proteoglycan , anatomy
Chronic cyclosporine (CsA) nephrotoxicity is characterized 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‐β (TGF‐β). Salt‐depleted rats were administered CsA, CsA + PFD, vehicle (VH) or VH + PFD and sacrificed at 28 days. Physiologic and histologic changes were studied in addition to TGF‐β1, plasminogen activator inhibitor‐1 (PAI‐1) and biglycan mRNA expressions by Northern blot. TGF‐β1 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‐β1, PAI‐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‐β1 protein expression by 80%. These results demonstrate that PFD can attenuate renal fibrosis in this model. PFD was associated with a decrease in TGF‐β1 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.