Pirfenidone treatment decreases transforming growth factor-beta1 and matrix proteins and ameliorates fibrosis in chronic cyclosporine nephrotoxicity.
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.
Shihab
Fuad S
FS
Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, USA. Fuad.Shihab@hsc.utah.edu
Bennett
William M
WM
Yi
Hong
H
Andoh
Takeshi F
TF
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
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