Effect of mycophenolate mofetil on nitric oxide production and inducible nitric oxide synthase gene expression during renal ischaemia-reperfusion injury

Abstract

Background. Recent animal data suggest that inducible nitric oxide synthase (iNOS) derived nitric oxide (NO) plays an important role in the pathogenesis of renal ischaemia-reperfusion injury (IRI) and that inhibition of iNOS ameliorates IRI. Mycophenolate mofetil (MMF), a lymphocyte selective anti-proliferative agent, has been shown to inhibit NO production in vitro. The aim of this study is to evaluate the effect of MMF on NO production and iNOS gene expression in vivo during renal IRI. Methods. Renal IRI was induced by clamping the left renal pedicle of male BALB/c mice for 30 min, followed by 15 min of reperfusion. The mice received placebo or MMF at 40, 80 or 120 mg/kg/day by oral gavage for 5 days before the operation. Sham-operated mice served as the operation control. The amount of NO produced and the level of iNOS gene expression in the kidney tissue during IRI was assessed by spin trapping electron paramagnetic resonance (EPR) spectroscopy and semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) respectively. Results. In the sham-operated kidneys, only low levels of NO and iNOS mRNA were detected. In mice with renal IRI, the amount of NO detected was significantly increased, which was reduced in a dose dependent fashion by pre-treatment with MMF. Pre-treatment with MMF also substantially reduced iNOS gene expression in the kidney tissue. Conclusions. We conclude that pre-treatment with MMF inhibits the production of NO and the induction of iNOS gene expression in the kidney during IRI. These results suggest that MMF might have the potential to ameliorate renal IRI.