Etomoxir-induced PPARα-modulated enzymes protect during acute renal failure
Etomoxir-induced PPARα-modulated enzymes protect during acute renal failure
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DOI：
10.1152/ajprenal.2000.278.4.f667
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发表时间：
2000-04-01
影响因子：
4.2
通讯作者：
Proia, AD
中科院分区：
文献类型：
--
作者：
Portilla, D;Dai, GH;Proia, AD
脂肪酸β -氧化（FAO）的调节是肾脏组织能量生产/利用持续平衡的重要机制。为了研究受刺激的FAO在缺血期间的作用，在缺血/再灌注（I/R）损伤诱导前5天给予依托莫西（Eto）、氯贝特和wy - 14643化合物。与给药的大鼠相比，Eto、clofibrate和wy治疗的大鼠在I/R损伤后血尿素氮和血清肌酐较低。组织学分析证实急性肾小管坏死明显改善。YR损伤导致acyl CoA氧化酶（AOX）和细胞色素P4A1 mRNA和蛋白水平降低3倍，酶活性抑制2倍。Eto处理阻止了IIR损伤期间mRNA和蛋白水平的降低以及这两种过氧化物酶体增殖激活受体α (PPAR α)靶基因的酶活性的抑制。与野生型对照相比，I/R损伤的PPAR α缺失小鼠表现出明显增强的皮质坏死和更差的肾功能。这些结果表明，PPAR α调控的FAO基因的上调在I/R损伤中观察到的细胞保护中起重要作用。
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. YR 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 (PPAR alpha) target genes during IIR injury. PPAR alpha 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 PPAR alpha-modulated FAO genes has an important role in the observed cytoprotection during I/R injury.