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

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)673-685
Number of pages13
JournalKidney International
Volume98
Issue number3
DOIs
Publication statusPublished - Sep 2020

All Science Journal Classification (ASJC) codes

  • Nephrology

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