Increased epoxyeicosatrienoic acid formation in the rat kidney during liver cirrhosis.
Increased epoxyeicosatrienoic acid formation in the rat kidney during liver cirrhosis.
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DOI：
10.1097/01.asn.0000076074.63334.99
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发表时间：
2003-07
期刊：
影响因子：
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通讯作者：
Motoaki Miyazono;Daling Zhu;R. Nemenoff;E. Jacobs;E. P. Carter
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文献类型：
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作者：
Motoaki Miyazono;Daling Zhu;R. Nemenoff;E. Jacobs;E. P. Carter
肝硬化的血管并发症通常很严重，尤其是肾脏。这些并发症是受伤的肝脏与其他器官（如肺、心脏和肾脏）之间复杂且知之甚少的相互作用的结果。本研究的目的是研究肝硬化期间肾脏血流动力学的改变，重点关注环氧二碳三烯酸（EET）的作用，已知它是肾脏血流动力学的有效调节剂。采用胆总管结扎术（CBDL）诱导大鼠肝硬化，并与假手术大鼠进行比较。实验在假手术或CBDL手术后4周进行。在离体灌注肾中评估血管反应性。Western blot检测cPLA(2)和细胞色素P450 （CYP450）的表达。用放射酶法测定cPLA(2)酶活性。采用高效液相色谱法测定EET产量。主要发现是CBDL大鼠的肾脏有明显更大的乙酰胆碱诱导的血管舒张，这种舒张被一氧化氮（NO）和前列腺素抑制部分阻断，被一氧化氮、前列腺素和CYP450代谢物联合抑制完全阻断。cPLA(2)在CBDL肾脏中的表达和活性增加，为CYP450酶提供花生四烯酸底物。最后，CYP450酶的表达和活性在CBDL肾脏中升高，导致血管舒张的11,12- eet和14,15- eet的产生显著增加。虽然有充分的证据表明，肝硬化期间肾脏血管收缩导致肾功能受损，但我们的数据清楚地表明，肝硬化肾脏中内源性EET的产生增加。这可能是一种维持肾脏灌注的稳态反应。
Vascular complications during liver cirrhosis are often severe, particularly in the kidney. These complications are the result of complex and poorly understood interactions between the injured liver and other organs such as the lungs, heart, and kidney. The purpose of this study was to investigate the alterations to renal hemodynamics during cirrhosis, focusing on the actions of epoxyeicosatrienoic acids (EET), known to be potent regulators of renal hemodynamics. Cirrhosis was induced in rats by common bile duct ligation (CBDL), and they were compared with sham rats. Experiments were conducted 4 wk after either the sham or CBDL surgery. Vasoreactivity was assessed in isolated perfused kidneys. cPLA(2) expression and cytochrome P450 (CYP450) expression were measured using Western blot. cPLA(2) enzymatic activity was measured by radioenzymatic assay. EET production was measured using rpHPLC analysis. The major findings were that kidneys from CBDL rats had significantly greater acetylcholine-induced vasodilation that was partially blocked by nitric oxide (NO) and prostaglandin inhibition and fully blocked by the combined inhibition of NO, prostaglandins, and CYP450 metabolites. Expression and activity of cPLA(2) in CBDL kidneys was increased, providing arachidonic acid substrate to the CYP450 enzymes. Finally, expression and activity of CYP450 enzymes was elevated in CBDL kidneys, resulting in significantly greater production of the vasodilating 11,12-EET and 14,15-EET. While it is well documented that renal vasoconstriction leading to impaired renal function occurs during cirrhosis, our data clearly demonstrate that endogenous production of EET is increased in cirrhotic kidneys. This may be a homeostatic response to preserve renal perfusion.