Etomoxir-induced PPAR alpha-modulated enzymes protect during acute renal failure

Regulation of fatty acid beta-oxidation (FAO) represents an important mecha nism for a sustained balance of energy production/utilization in kidney tis sue. To examine the role of stimulated FAO during ischemia, Etomoxir (Eto), clofibrate, and WY-14,643 compounds were given 5 days prior to the inducti on of ischemia/reperfusion (I/R) injury. Compared with rats administered ve hicle, Eto-, clofibrate-, and WY-treated rats had lower blood urea nitrogen and serum creatinines following I/R injury. Histological analysis confirme d a significant amelioration of acute tubular necrosis. YR injury led to a threefold reduction of mRNA and protein levels of acyl CoA oxidase (AOX) an d cytochrome P4A1, as well as twofold inhibition of their enzymatic activit ies. Eto treatment prevented the reduction of mRNA and protein levels and t he inhibition of the enzymatic activities of these two peroxisome prolifera tor-activated receptor-alpha (PPAR alpha) target genes during IIR injury. P PAR alpha null mice subjected to I/R injury demonstrated significantly enha nced cortical necrosis and worse kidney function compared with wild-type co ntrols. These results suggest that upregulation of PPAR alpha-modulated FAO genes has an important role in the observed cytoprotection during I/R inju ry.