Asymmetric dimethylarginine accumulates in the kidney during ischemia/reperfusion injury.
Asymmetric dimethylarginine accumulates in the kidney during ischemia/reperfusion injury.
复制标题
在缺血/再灌注损伤期间，非对称二甲基精氨酸在肾脏中积聚。
DOI：
10.1038/ki.2013.398
复制
发表时间：
2014-03
影响因子：
19.6
通讯作者：
中科院分区：
文献类型：
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作者：
缺血/再灌注损伤是急性肾小管坏死的主要原因。一氧化氮对缺血/再灌注损伤具有保护作用;然而，一氧化氮合酶的内源性抑制剂不对称二甲基精氨酸（ADMA）在缺血/再灌注损伤中的作用尚不清楚。ADMA由蛋白质精氨酸甲基转移酶（PRMT）产生，主要由二甲基精氨酸二甲氨基水解酶（DDAH）降解。在这里，我们研究了缺血/再灌注损伤小鼠肾脏中ADMA和PRMT和DDAH表达的动力学。损伤后，DDAH-1水平下降，肾脏和血浆ADMA值增加与肾功能不全。肾脏ADMA与氧化应激标志物8-羟基-2 ′-脱氧鸟苷相关。抗氧化剂，N-乙酰半胱氨酸，或蛋白酶体抑制剂，MG-132，恢复这些变化。输注降压剂量的ADMA加重了缺血/再灌注损伤野生小鼠肾脏的肾功能障碍、毛细血管损失和肾小管坏死，而DDAH转基因小鼠的损伤则减弱。因此，缺血/再灌注损伤诱导的氧化应激可减少DDAH表达并引起ADMA蓄积，这可能导致肾脏毛细血管损失和肾小管坏死。
Ischemia/reperfusion injury is the leading cause of acute tubular necrosis. Nitric oxide has a protective role against ischemia/reperfusion injury; however, the role of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, in ischemia/reperfusion injury remains unclear. ADMA is produced by protein arginine methyltransferase (PRMT) and is mainly degraded by dimethylarginine dimethylaminohydrolase (DDAH). Here we examined the kinetics of ADMA and PRMT and DDAH expression in the kidneys of ischemia/reperfusion-injured mice. After the injury, DDAH-1 levels were decreased and renal and plasma ADMA values were increased in association with renal dysfunction. Renal ADMA was correlated with 8-hydroxy-2′-deoxyguanosine, a marker of oxidative stress. An antioxidant, N-acetylcysteine, or a proteasomal inhibitor, MG-132, restored these alterations. Infusion of subpressor dose of ADMA exacerbated renal dysfunction, capillary loss, and tubular necrosis in the kidneys of ischemia/reperfusion-injured wild mice, while damage was attenuated in DDAH transgenic mice. Thus, ischemia/reperfusion injury–induced oxidative stress may reduce DDAH expression and cause ADMA accumulation, which may contribute to capillary loss and tubular necrosis in the kidney.