IDH2 gene deficiency accelerates unilateral ureteral obstructioninduced kidney inflammation through oxidative stress and activation of macrophages
Jee In Kim1, Mi Ra Noh2, Ga-Eun Yoon1, Hee-Seong Jang2, Min Jung Kong2, and Kwon Moo Park2,*
1Department of Molecular Medicine and Medical Research Center, Keimyung University School of Medicine, Daegu 42601, 2Department of Anatomy and BK21 Plus, School of Medicine, Kyungpook National University, Daegu 41944, Korea
Received: August 27, 2020; Revised: November 17, 2020; Accepted: December 11, 2020
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Mitochondrial NADP+-dependent isocitrate dehydrogenase 2 (IDH2) produces NADPH, which is known to inhibit mitochondrial oxidative stress. Ureteral obstruction induces kidney inflammation and fibrosis via oxidative stress. Here, we investigated the role and underlying mechanism of IDH2 in unilateral ureteral obstruction (UUO)-induced kidney inflammation using IDH2 gene deleted mice (IDH2–/–). Eight- to 10-week-old female IDH2–/– mice and wild type (IDH2+/+) littermates were subjected to UUO and kidneys were harvested 5 days after UUO. IDH2 was not detected in the kidneys of IDH2–/– mice, while UUO decreased IDH2 in IDH2+/+ mice. UUO increased the expressions of markers of oxidative stress in both IDH2+/+ and IDH2–/– mice, and these changes were greater in IDH2–/– mice compared to IDH2+/+ mice. Bone marrow-derived macrophages of IDH2–/– mice showed a more migrating phenotype with greater ruffle formation and Rac1 distribution than that of IDH2+/+ mice. Correspondently, UUO-induced infiltration of monocytes/macrophages was greater in IDH2–/– mice compared to IDH2+/+ mice. Taken together, these data demonstrate that IDH2 plays a protective role against UUO-induced inflammation through inhibition of oxidative stress and macrophage infiltration.