The role and regulatory mechanism of arginase 2 for acute kidney injury

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K09701
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Kidney internal medicine
• Research Institution: Kyushu University
• Principal Investigator: TORISU KUMIKO 九州大学, 医学研究院, 准教授 (20448434)
• Co-Investigator(Kenkyū-buntansha): 鶴屋 和彦 奈良県立医科大学, 医学部, 教授 (20372740) ; 升谷 耕介 福岡大学, 医学部, 准教授 (30419593)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: アルギナーゼ / アルギニン / ニトロ化ストレス / 急性腎障害 / 虚血再灌流障害

Outline of Final Research Achievements

Arginase 2 (Arg2) is an enzyme which degrades L-arginine. Arg2 is highly expressed in the kidney, but its importance is unknown. ARG2 was predominantly expressed in renal tubules of the cortex region, 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. Additionally, an accumulation of 3-nitrotyrosine and apoptosis of renal tubule cells were attenuated in Arg2 knockout mice. Inhibition of arginase by Nω-hydroxy-nor-L-arginine alleviated kidney ischemia/reperfusion injury like the results found in Arg2 knockout mice.

Free Research Field

活性酸素ストレスの制御

Academic Significance and Societal Importance of the Research Achievements

腎臓の虚血再灌流障害は急性腎障害の主たる原因である。腎臓が虚血に曝されると活性酸素種や活性窒素種が過剰に産生され腎障害を増悪させる。アルギナーゼ２は一酸化窒素合成酵素と競合してL-アルギニンを分解し、活性窒素種の産生を制御している。我々の研究結果から、アルギナーゼ２は腎臓で発現が高く、腎臓の虚血再灌流障害によって発現が亢進し、アルギナーゼ２を抑制することで虚血再灌流障害を軽減することができた。アルギナーゼ２は虚血再灌流障害による急性腎障害において活性窒素種の制御に中心的な役割を担っていることが示唆された。よってアルギナーゼ２に特異的な阻害剤があれば腎臓の虚血再灌流障害の治療として期待できる。