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.


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.
Brook
Nicholas R
NR
The University Department of Surgery, Leicester, UK. nicholasbrook@fastmail.fm
Waller
Julian R
JR
Bicknell
Gareth R
GR
Nicholson
Michael L
ML
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D024061:Collagen Type III / Q000187:drug effects* / Q000378:metabolism; D017364:Collagenases / Q000187:drug effects* / Q000378:metabolism; D005355:Fibrosis / Q000139:chemically induced; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000009:adverse effects; D007674:Kidney Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000187:drug effects / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000187:drug effects / Q000378:metabolism; D011728:Pyridones / Q000494:pharmacology*; D012333:RNA, Messenger / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D016559:Tacrolimus / Q000009:adverse effects*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000187:drug effects* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000187:drug effects* / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D024061:Collagen Type III; D007166:Immunosuppressive Agents; D011728:Pyridones; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D016212:Transforming Growth Factor beta; C093844:pirfenidone; D017364:Collagenases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D016559:Tacrolimus