Effect of pirfenidone on apoptosis-regulatory genes in chronic cyclosporine nephrotoxicity

Fuad S. Shihab, William M. Bennett, Hong Yi, Takeshi F. Andoh

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

Abstract

Background. Apoptosis was shown to play a role in the progression of fibrosis in a chronic cyclosporine A (CsA) nephrotoxicity animal model. In addition, the antifibrotic molecule pirfenidone (PFD) was shown to ameliorate fibrosis in this model. We evaluated the role of PFD on the expression of apoptosis-regulatory genes in the kidneys of CsA-treated rats. Methods. Rats were administered CsA 7.5 mg/kg per day, CsA+PFD (250 mg/kg/day), vehicle (VH), or VH + PFD, and sacrificed at 28 days. Physiologic and histologic changes were studied, and apoptosis was detected by terminal deoxynucleotide transferase-mediated dUTP nick-end labeling stain. The mRNA expression of pro-apoptotic genes p53 and Fas-ligand was evaluated by quantitative polymerase chain reaction, and that of Bcl-xL, an anti-apoptotic gene, was evaluated by Northern blot analysis. In addition to mRNA expression, immunohistochemical studies of caspase 3 were performed. Result. PFD administration to CsA-treated rats significantly ameliorated nephrotoxicity. Apoptosis-positive cells were increased by CsA but significantly reduced by PFD treatment (68±19 vs. 3±1, P<0.01). In addition, PFD down-regulated the mRNA expression of CsA-induced p53 and Fas-ligand (P<0.01) and increased that of Bcl-xL, previously reduced by CsA (P<0.01). Finally, PFD significantly down-regulated caspase 3 expression, present mostly on renal tubular epithelial cells. None of these changes were observed in VH-treated rats. Conclusion. Whereas CsA favored the expression of pro-apoptotic genes, that effect was ameliorated by PFD. Because apoptosis can partly explain the loss of cells associated with fibrosis, the influence of PFD on apoptosis-regulatory genes in a manner that reduces apoptosis may explain some of its antifibrotic properties.

Original languageEnglish (US)
Pages (from-to)419-426
Number of pages8
JournalTransplantation
Volume79
Issue number4
DOIs
StatePublished - Feb 27 2005
Externally publishedYes

ASJC Scopus subject areas

  • Transplantation

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