Mitochondrial NADP+-Dependent Isocitrate Dehydrogenase Deficiency Exacerbates Mitochondrial and Cell Damage after Kidney Ischemia-Reperfusion Injury.
Mitochondrial NADP+-dependent isocitrate dehydrogenase (IDH2) catalyzes the oxidative decarboxylation of isocitrate toα-ketoglutarate, synthesizing NADPH, which is essential for mitochondrial redox balance. Ischemia-reperfusion (I/R) is one of most common causes of AKI. I/R disrupts the mitochondrial redox balance, resulting in oxidative damage to mitochondria and cells. Here, we investigated the role of IDH2 in I/R-induced AKI. I/R injury in mice led to the inactivation of IDH2 in kidney tubule cells.Idh2gene deletion exacerbated the I/R-induced increase in plasma creatinine and BUN levels and the histologic evidence of tubule injury, and augmented the reduction of NADPH levels and the increase in oxidative stress observed in the kidney after I/R. Furthermore,Idh2gene deletion exacerbated I/R-induced mitochondrial dysfunction and morphologic fragmentation, resulting in severe apoptosis in kidney tubule cells. In cultured mouse kidney proximal tubule cells,Idh2gene downregulation enhanced the mitochondrial damage and apoptosis induced by treatment with hydrogen peroxide. This study demonstrates thatIdh2gene deletion exacerbates mitochondrial damage and tubular cell deathviaincreased oxidative stress, suggesting that IDH2 is an important mitochondrial antioxidant enzyme that protects cells from I/R insult.
Department of Anatomy, Cardiovascular Research Institute and Brain Korea 21 Plus, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
Sang Jun
SJ
Han
Department of Anatomy, Cardiovascular Research Institute and Brain Korea 21 Plus, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
Hee-Seong
HS
Jang
Department of Anatomy, Cardiovascular Research Institute and Brain Korea 21 Plus, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
Mi Ra
MR
Noh
Department of Anatomy, Jeju National University School of Medicine, Jeju-Do, Republic of Korea.
Jinu
J
Kim
Department of Anatomy, Cardiovascular Research Institute and Brain Korea 21 Plus, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
Min Jung
MJ
Kong
Department of Molecular Medicine and Medical Research Center, College of Medicine, Keimyung University, Daegu, Republic of Korea; and.
Jee In
JI
Kim
Department of Biochemistry, School of Life Sciences and Biotechnology, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea kmpark@knu.ac.kr parkjw@knu.ac.kr.
Jeen-Woo
JW
Park
Department of Anatomy, Cardiovascular Research Institute and Brain Korea 21 Plus, Kyungpook National University School of Medicine, Daegu, Republic of Korea; kmpark@knu.ac.kr parkjw@knu.ac.kr.
Kwon Moo
KM
Park
D058186:Acute Kidney Injury / Q000201:enzymology / Q000209:etiology; D000818:Animals; D017209:Apoptosis; D016923:Cell Death; D002478:Cells, Cultured; D017353:Gene Deletion; D007521:Isocitrate Dehydrogenase / Q000172:deficiency* / Q000235:genetics; D007668:Kidney / Q000098:blood supply* / Q000201:enzymology*; D007684:Kidney Tubules / Q000473:pathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000201:enzymology*; D015427:Reperfusion Injury / Q000201:enzymology*
D007521:Isocitrate Dehydrogenase; C000599591:isocitrate dehydrogenase 2, mouse
Kidney ischemia reperfusion; Mitochondrial isocitrate dehydrogenase; NADPH; Reactive oxidative species