Arginase 2 is a mediator of ischemia-reperfusion injury in the kidney through regulation of nitrosative stress
Arginase 2 is a mediator of ischemia-reperfusion injury in the kidney through regulation of nitrosative stress
复制标题
DOI：
10.1016/j.kint.2020.03.032
复制
发表时间：
2020-09-01
影响因子：
19.6
通讯作者：
Kitazono, Takanari
中科院分区：
文献类型：
--
作者：
Hara, Masatoshi;Torisu, Kumiko;Kitazono, Takanari
肾缺血再灌注损伤是急性肾损伤（AKI）的主要原因。肾灌注减少后，病理性活性氧和活性氮的过量产生在肾缺血再灌注损伤的发生发展中起重要作用。精氨酸酶2 （ARG2）与一氧化氮合酶竞争相同的底物l -精氨酸，并参与活性氮的调节。因此，我们利用人近端小管细胞（HK-2）和小鼠肾缺血再灌注损伤模型来研究ARG2在肾缺血再灌注损伤中的作用。ARG2主要表达于肾皮质小管，缺血再灌注损伤后表达量增加。在HK-2细胞中，ARG2在细胞质中以点状表达，在缺氧复氧后表达上调。与对照siRNA相比，ARG2敲低降低了缺氧再氧化损伤后活性氧和3-硝基酪氨酸的水平。与上述结果一致的是，Arg2基因敲除小鼠的肾功能异常和缺血再灌注损伤引起的急性肾小管坏死评分升高明显降低，血压无明显变化。此外，与野生型小鼠相比，Arg2敲除小鼠的3-硝基酪氨酸积累和肾小管细胞凋亡减少。n -omega-羟基-非l -精氨酸对精氨酸酶的抑制减轻了与Arg2敲除小鼠相似的肾缺血再灌注损伤。因此，ARG2通过亚硝化应激在缺血再灌注诱导的AKI中起关键作用。因此，arg2特异性抑制剂可有效治疗肾缺血再灌注损伤。
Kidney ischemia-reperfusion injury is a major cause of acute kidney injury (AKI). Following reduced kidney perfusion, the pathological overproduction of reactive oxygen and reactive nitrogen species play a substantial role in the development of kidney ischemia-reperfusion injury. Arginase 2 (ARG2) competes with nitric oxide synthase for the same substrate, L-arginine, and is implicated in the regulation of reactive nitrogen species. Therefore, we investigated the role of ARG2 in kidney ischemia-reperfusion injury using human proximal tubule cells (HK-2) and a mouse model of kidney ischemia-reperfusion injury. ARG2 was predominantly expressed in kidney tubules of the cortex, which was increased after ischemia-reperfusion injury. In HK-2 cells, ARG2 was expressed in punctate form in the cytoplasm and upregulated after hypoxia-reoxygenation. ARG2 knockdown reduced the level of reactive oxygen species and 3-nitrotyrosine after hypoxia-reoxygenation injury compared with control siRNA. Consistent with these results, in Arg2 knockout mice, abnormal kidney function and the increased acute tubular necrosis score induced by ischemia-reperfusion injury was significantly reduced without any obvious blood pressure changes. Additionally, an accumulation of 3-nitrotyrosine and apoptosis of renal tubule cells were attenuated in Arg2 knockout mice compared with wild-type mice. Inhibition of arginase by N-omega-hydroxy-nor-L-arginine alleviated kidney ischemia-reperfusion injury like the results found in Arg2 knockout mice. Thus, ARG2 plays a pivotal role in ischemia- reperfusion-induced AKI by means of nitrosative stress. Hence, an ARG2-specific inhibitor may effectively treat kidney ischemia-reperfusion injury.