Peroxisome Proliferator-Activated Receptor- Contributes to the Resolution of Inflammation after Renal Ischemia/Reperfusion Injury

This study was designed to elucidate the role of peroxisome proliferator-activated receptor (PPAR)in the development of inflammation after ischemia/reperfusion injury of the kidney. We have evaluated the effects of ischemia/reperfusion on renal dysfunction, injury, and inflammation in wild-type mice or mice in which the gene for PPARhas been deleted [PPAR( / )] and then treated with the PPARagonist fenofibrate. Mice were subjected to bilateral renal ischemia (30 min) and reperfusion (24 h) and received fenofibrate (3 mg/kg i.p.) before reperfusion. Plasma creatinine, urea, and aspartate aminotransferase were all used as indicators of renal dysfunction and injury. Kidneys were used for histological and immunohistochemical analysis and markers of inflammation. Fenofibrate significantly attenuated the degree of renal dysfunction, injury, and inflammation caused by ischemia/reperfusion injury. The degree of renal dysfunction, injury, and inflammation caused by ischemia/reperfusion was also significantly augmented in PPAR( / ) mice compared with their wild-type littermates. It is interesting that fenofibrate did not protect PPAR( / ) mice against ischemia/reperfusion injury. Therefore, we propose that ligands of PPARmay be useful in the treatment of renal ischemia/reperfusion injury and that endogenous PPARlimits the degree of renal dysfunction, injury, and inflammation associated with ischemia/reperfusion injury. Peroxisome proliferator-activated receptor (PPAR)is a member of the nuclear receptor superfamily of ligand-dependent transcription factors related to retinoid, steroid, and thyroid hormone receptors (Evans, 1988). The structure of PPAR(and PPARand PPAR) consists of an aminoterminal region that allows for ligand-independent activation and constitutive activity on the receptor and is negatively regulated by phosphorylation. This region is followed by a DNA binding domain (two zinc finger motifs separated by a linker region) and the carboxyl-terminal ligand binding domain (Moras and Gronemeyer, 1998). The role of PPARexpression in the kidney is not yet fully understood, but it is known that PPARexpression predominates in the proximal convoluted tubule and the thick limb of the loop of Henle, which could contribute to dietary lipid-induced gene expression of peroxisomal and mitochondrial fatty acid oxidation enzymes in these segments (Guan et al., 1997; Ouali et al.,