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

Kidney Int. 2020 Sep;98(3):673-685. doi: 10.1016/j.kint.2020.03.032. Epub 2020 Apr 25.


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.

Keywords: NOS uncoupling; arginase 2; ischemia–reperfusion injury; kidney; nitrosative stress; nor-NOHA; stimulated emission depletion microscopy (STED).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Kidney Injury*
  • Animals
  • Arginase / genetics
  • Arginase / metabolism
  • Kidney / metabolism
  • Mice
  • Nitrosative Stress
  • Reperfusion Injury*


  • Arg2 protein, mouse
  • Arginase