Arginase 2 is a mediator of ischemia-reperfusion injury in the kidney through regulation of nitrosative stress.

Masatoshi Hara, Kumiko Torisu, Keigo Tomita, Yasuhiro Kawai, Kazuhiko Tsuruya, Toshiaki Nakano, Takanari Kitazono

Kidney international 2020 Sep

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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 Nω-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. Copyright © 2020 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Citation

Masatoshi Hara, Kumiko Torisu, Keigo Tomita, Yasuhiro Kawai, Kazuhiko Tsuruya, Toshiaki Nakano, Takanari Kitazono. Arginase 2 is a mediator of ischemia-reperfusion injury in the kidney through regulation of nitrosative stress. Kidney international. 2020 Sep;98(3):673-685