Etomoxir-induced PPARalpha-modulated enzymes protect during acute renal failure.
Regulation of fatty acid beta-oxidation (FAO) represents an important mechanism for a sustained balance of energy production/utilization in kidney tissue. To examine the role of stimulated FAO during ischemia, Etomoxir (Eto), clofibrate, and WY-14,643 compounds were given 5 days prior to the induction of ischemia/reperfusion (I/R) injury. Compared with rats administered vehicle, Eto-, clofibrate-, and WY-treated rats had lower blood urea nitrogen and serum creatinines following I/R injury. Histological analysis confirmed a significant amelioration of acute tubular necrosis. I/R injury led to a threefold reduction of mRNA and protein levels of acyl CoA oxidase (AOX) and cytochrome P4A1, as well as twofold inhibition of their enzymatic activities. Eto treatment prevented the reduction of mRNA and protein levels and the inhibition of the enzymatic activities of these two peroxisome proliferator-activated receptor-alpha (PPARalpha) target genes during I/R injury. PPARalpha null mice subjected to I/R injury demonstrated significantly enhanced cortical necrosis and worse kidney function compared with wild-type controls. These results suggest that upregulation of PPARalpha-modulated FAO genes has an important role in the observed cytoprotection during I/R injury.
Portilla
D
D
Division of Nephrology, Department of Internal Medicine, University of Arkansas for Medical Sciences and John McClellan Memorial Veterans Hospital, Little Rock, Arkansas 72205, USA. portilladicier@exchange.vams.edu
Dai
G
G
Peters
J M
JM
Gonzalez
F J
FJ
Crew
M D
MD
Proia
A D
AD
D058186:Acute Kidney Injury / Q000097:blood / Q000201:enzymology* / Q000473:pathology; D000818:Animals; D001806:Blood Urea Nitrogen; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors; D002994:Clofibrate / Q000494:pharmacology; D003404:Creatinine / Q000097:blood; D004798:Enzymes / Q000502:physiology*; D004852:Epoxy Compounds / Q000494:pharmacology*; D007511:Ischemia / Q000473:pathology / Q000503:physiopathology; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D009336:Necrosis; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000502:physiology*; D012079:Renal Circulation; D015427:Reperfusion Injury / Q000473:pathology / Q000503:physiopathology; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
D004798:Enzymes; D004852:Epoxy Compounds; D011743:Pyrimidines; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C006253:pirinixic acid; D003404:Creatinine; D002334:Carnitine O-Palmitoyltransferase; D002994:Clofibrate; C054207:etomoxir