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

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. (c) 2005 Elsevier Inc. All rights reserved.