The experimental agent pirfenidone reduces pro-fibrotic gene expression in a model of tacrolimus-induced nephrotoxicity

J Surg Res. 2005 May 15;125(2):137-43. doi: 10.1016/j.jss.2004.12.007.


Background: Tacrolimus nephrotoxicity is thought to contribute to renal allograft dysfunction and subsequent failure, a process that is underpinned by alterations in mRNA expression of genes involved in matrix metabolism. The new anti-fibrotic pirfenidone was tested for its potential to reverse markers of renal dysfunction.

Materials and methods: Rats were salt-depleted before tacrolimus and pirfenidone treatment. Serum creatinine, urinary protein/creatinine ratio, extracellular matrix deposition (ECM), and mRNA expression of genes involved in matrix turnover were assessed.

Results: Tacrolimus reduced TGF-beta mRNA expression below control levels and treatment with pirfenidone at all doses did not alter this effect. Likewise, TIMP-1 mRNA expression was depressed by the addition of tacrolimus and pirfenidone caused a further decrease in expression. Collagen III, MMP-2, and MMP-9 expression was unchanged by tacrolimus, but pirfenidone reduced collagen III below control levels. ECM was slight (1-4%) and not significantly different between groups.

Conclusions: These findings suggest that pirfenidone can attenuate the limited fibrotic potential of tacrolimus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Collagen Type III / drug effects*
  • Collagen Type III / metabolism
  • Collagenases / drug effects*
  • Collagenases / metabolism
  • Fibrosis / chemically induced
  • Gene Expression Regulation, Enzymologic / drug effects
  • Immunosuppressive Agents / adverse effects
  • Kidney Diseases / chemically induced
  • Kidney Diseases / metabolism*
  • Kidney Diseases / pathology
  • Male
  • Matrix Metalloproteinase 2 / drug effects
  • Matrix Metalloproteinase 2 / metabolism
  • Matrix Metalloproteinase 9 / drug effects
  • Matrix Metalloproteinase 9 / metabolism
  • Pyridones / pharmacology*
  • RNA, Messenger / drug effects
  • Rats
  • Rats, Sprague-Dawley
  • Tacrolimus / adverse effects*
  • Tissue Inhibitor of Metalloproteinase-1 / drug effects*
  • Tissue Inhibitor of Metalloproteinase-1 / metabolism
  • Transforming Growth Factor beta / drug effects*
  • Transforming Growth Factor beta / metabolism


  • Anti-Inflammatory Agents, Non-Steroidal
  • Collagen Type III
  • Immunosuppressive Agents
  • Pyridones
  • RNA, Messenger
  • Tissue Inhibitor of Metalloproteinase-1
  • Transforming Growth Factor beta
  • pirfenidone
  • Collagenases
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9
  • Tacrolimus