The selective PPARgamma 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 (PPARgamma) 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 PPARgamma, rather than an up-regulation of PPARgamma 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 PPARgamma 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 PPARgamma1 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 PPARgamma1 mRNA levels compared to sham animals, which were unchanged in rats pretreated with LPS.


CONCLUSIONS
We document here for the first time that endogenous ligands of PPARgamma may contribute to the protection against renal I/R injury afforded by LPS pretreatment in the rat.
Collino
Massimo
M
Centre for Experimental Medicine, Nephrology and Critical Care, William Harvey Research Institute, St. Bartholomew's and The Royal London School of Medicine and Dentistry, Queen Mary-University of London, London, UK.
Patel
Nimesh S A
NS
Lawrence
Kevin M
KM
Collin
Marika
M
Latchman
David S
DS
Yaqoob
Muhammad M
MM
Thiemermann
Christoph
C
D000813:Anilides / Q000494:pharmacology*; D000818:Animals; D004347:Drug Interactions; D007674:Kidney Diseases / Q000188:drug therapy* / Q000503:physiopathology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D047495:PPAR gamma / Q000037:antagonists & inhibitors* / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000503:physiopathology
C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D008070:Lipopolysaccharides; D047495:PPAR gamma; D012333:RNA, Messenger