Previous studies have demonstrated that levels of tumor necrosis factor-alpha (TNF-alpha) or its mRNA expression are increased in acute renal failure of various types including ischemia/reperfusion injury. This study was undertaken to determine whether pentoxifylline (PTX), an inhibitor of TNF-alpha production, provides a protective effect against ischemic acute renal failure in rabbits. Renal ischemia was induced by clamping bilateral renal arteries for 60 min. Animals were pretreated with PTX (30 mg/kg, i.v.) 10 min before release of clamp. At 24 h of reperfusion of blood after ischemia, changes in renal function, renal blood flow, and the expression of TNF-alpha mRNA were evaluated. Ischemia/reperfusion caused a marked reduction in GFR, which was accompanied by an increase of serum creatinine levels. Such changes were significantly attenuated by PTX pretreatment. PTX ameliorated the impairment of renal tubular function, but it had no effect on the reduction of renal blood flow induced by ischemia/reperfusion. The protective effect of PTX on functional changes was supported by morphological studies. The impairment of glucose and phosphate reabsorption in postischemic kidneys was associated with a depression in the expression of Na+-glucose and Na+-Pi transporters. The expression of TNF-alpha mRNA was increased after reperfusion, which was inhibited by PTX pretreatment. The PTX pretreatment in vitro prevented the release of lactate dehydrogenase induced by an oxidant t-butylhydroperoxide in rabbit renal cortical slices, but it did not produce any effect on the oxidant-induced lipid peroxidation, suggesting that PTX protection is not resulted from its antioxidant action. These results suggest that PTX may exert a protective effect against ischemic acute renal failure by inhibiting the production of TNF-alpha in rabbits.

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