Protective Effects of Peroxisome Proliferator-Activated Receptor γ Ligand on Apoptosis and Hepatocyte Growth Factor Induction in Renal Ischemia-Reperfusion Injury

Abstract

Renal ischemia-reperfusion injury affects the long-term outcome of renal graft survival. Thiazolidinediones (TZDs), synthetic peroxisome proliferator-activated receptor (PPAR)-gamma ligands, have been shown to exert therapeutic effects upon renal ischemia-reperfusion injury far beyond their use as insulin sensitizers. It has also been reported that hepatocyte growth factor (HGF) has a beneficial effect on renal ischemia-reperfusion injury and that TZDs induce increased HGF mRNA expression and protein secretion. We investigated the effect of troglitazone, one of the TZDs, in a rat model of renal ischemia-reperfusion injury. A 45-minute period of warm renal ischemia was induced by bilateral clamping at 37 degrees C with rats being sacrificed before the onset of ischemia and at 2, 4, 6, and 12 hr after reperfusion. The expression of PPAR-gamma was measured by reverse-transcriptase polymerase chain reaction (RT-PCR) and western blotting while the production of HGF was investigated by RT-PCR and immunohistochemistry. The effect of troglitazone treatment on the level of apoptosis was determined by staining for cleaved caspase-3 and single-stranded DNA (ssDNA). The numbers of cleaved caspase-3 and ssDNA positive cells were decreased in rats treated with troglitazone. The production of HGF mRNA and protein was most intense at 4 hr. The expression of PPAR-gamma and HGF was increased in the group treated with troglitazone compared with the control group. CONCLUSIONS.: Pretreatment of rats with the PPAR-gamma ligand troglitazone decreased apoptotic cell death in renal ischemia-reperfusion injury as a result of the induction of HGF.