title: Pirfenidone treatment decreases transforming growth factor-beta1 and matrix proteins and ameliorates fibrosis in chronic cyclosporine nephrotoxicity.
abstract: 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-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 (PAI-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, 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-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.
authors.affiliation: Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, USA. Fuad.Shihab@hsc.utah.edu
authors.forename: Fuad S
authors.initials: FS
authors.lastname: Shihab
authors.forename: William M
authors.initials: WM
authors.lastname: Bennett
authors.forename: Hong
authors.initials: H
authors.lastname: Yi
authors.forename: Takeshi F
authors.initials: TF
authors.lastname: Andoh
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D058578:Biglycan; D002114:Calcinosis / Q000139:chemically induced / Q000473:pathology*; D003404:Creatinine / Q000097:blood / Q000378:metabolism; D016572:Cyclosporine / Q000493:pharmacokinetics / Q000633:toxicity*; D016326:Extracellular Matrix Proteins / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced / Q000473:pathology*; D007684:Kidney Tubules / Q000187:drug effects / Q000473:pathology*; D008297:Male; D011509:Proteoglycans / Q000235:genetics; D011728:Pyridones / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D014158:Transcription, Genetic / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000032:analysis / Q000502:physiology*; D053773:Transforming Growth Factor beta1
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; C546884:BGN protein, human; C546886:Bgn protein, rat; D058578:Biglycan; D016326:Extracellular Matrix Proteins; D007166:Immunosuppressive Agents; D011509:Proteoglycans; D011728:Pyridones; D012333:RNA, Messenger; C508960:TGFB1 protein, human; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D016572:Cyclosporine; D003404:Creatinine; C093844:pirfenidone