TY - JOUR
T1 - Etomoxir-induced PPARα-modulated enzymes protect during acute renal failure
AU - Portilla, Didier
AU - Dai, Gonghe
AU - Peters, Jeffrey M.
AU - Gonzalez, Frank J.
AU - Crew, Mark D.
AU - Proia, Alan D.
PY - 2000/4
Y1 - 2000/4
N2 - Regulation of fatty acid β-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-α (PPARα) target genes during I/R injury. PPARα 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 PPARα- modulated FAO genes has an important role in the observed cytoprotection during I/R injury.
AB - Regulation of fatty acid β-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-α (PPARα) target genes during I/R injury. PPARα 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 PPARα- modulated FAO genes has an important role in the observed cytoprotection during I/R injury.
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U2 - 10.1152/ajprenal.2000.278.4.f667
DO - 10.1152/ajprenal.2000.278.4.f667
M3 - Article
C2 - 10751229
AN - SCOPUS:0034169551
VL - 278
SP - F667-F675
JO - American Journal of Physiology - Renal Physiology
JF - American Journal of Physiology - Renal Physiology
SN - 0363-6127
IS - 4 47-4
ER -