The selective PPARγ antagonist GW9662 reverses the protection of LPS in a model of renal ischemia-reperfusion

Background. We have recently reported that pretreatment of rats with endotoxin ( lipopolysaccharide, LPS) and selective agonists of the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPAR gamma) protect the kidney against ischemia/reperfusion (I/R) injury. Here we investigate the hypothesis that the renoprotective effects of LPS may be due to an enhanced formation of endogenous ligands of PPAR gamma, rather than an up-regulation of PPAR gamma expression. Methods. Rats were pretreated with LPS ( 1 mg/ kg, IP, 24 hours prior to ischemia) in the absence ( control) or presence of the selective PPAR gamma antagonist GW9662 ( 1 mg/ kg, IP, 24 and 12 hours prior to ischemia). Twenty-four hours after injection of LPS, rats were subjected to 60 minutes of bilateral renal ischemia, followed by 6 hours of reperfusion. Serum and urinary indicators of renal injury and dysfunction were measured, specifically serum creatinine, aspartate aminotransferase, and gamma-glutamyl-transferase, creatinine clearance, urine flow, and fractional excretion of sodium. Kidney PPAR gamma 1 mRNA levels were determined by reverse transcriptase-polymerase chain reaction. Results. Pretreatment with LPS significantly attenuated all markers of renal injury and dysfunction caused by I/R. Most notably, GW9662 abolished the protective effects of LPS. Additionally, I/R caused an up-regulation of kidney PPAR gamma 1mRNA levels compared to sham animals, which were unchanged in rats pretreated with LPS. Conclusion. We document here for the first time that endogenous ligands of PPAR gamma may contribute to the protection against renal I/R injury afforded by LPS pretreatment in the rat.