Pentoxifylline (PTX) ameliorates acute renal ischemia‐reperfusion (IR) injury

Abstract

We have previously demonstrated that, in vitro, c‐AMP specific PDE3 inhibitors block mitogenesis of mesangial cells (Am J Physiol Renal Physiol, 2004) and PDE4 inhibitors block cytokine stimulated MCP‐1 expression (Am J Physiol Cell Physiol, 2005). The in vivo relevance of these findings has not been previously established. Mice were treated with the nonselective cAMP PDE inhibitor pentoxifylline (PTX) prior to bilateral clamping of the renal arteries for 30 minutes, followed by reperfusion for 1 and 4 days. PTX blunted the increase in BUN and creatinine after 1 day (−38% and −43%, respectively, p<0.05), and after 4 days (−80% and −44%, respectively, p<0.05). PTX reduced the extent of tubular necrosis (1 day: 39.13% vs. 52.5%; 4 days: 2.5% vs. 23.33%, p<0.05, p=NS. % cortical area in PTX vs. IR). PTX reduced PCNA expression 4 days after IR, as assessed by Western blot (−43%, p<0.05), and reduced caspase 3 activity one day after IR (−43%, p<0.05). PTX markedly reduced expression of MMP10 and Cox‐2 one day after IR (26 and 4 folds, respectively, p<0.05), which are induced in response to acute inflammation. PTX significantly reduced cyclin F, cyclin A2 and Ki67 expression 4 days after IR (124, 7 and 9 folds, respectively, p<0.05), which are induced in response to proliferation. We conclude that PTX ameliorates IR injury through c‐AMP mediated reduction in proliferative and inflammatory responses to acute injury.