Protection of Ndrg2 deficiency on renal ischemia-reperfusion injury via activating PINK1/Parkin-mediated mitophagy  

作　　者：Min Liu Jianwen Chen Miao Sun Lixia Zhang Yao Yu Weidong Mi Yulong Ma Guyan Wang 

机构地区：[1]Department of Anesthesiology,Beijing Tongren Hospital,Capital Medical University,Beijing 100730,China [2]Department of Nephrology,The First Medical Center of Chinese PLA General Hospital,Nephrology Institute of the Chinese People’s Liberation Army,State Key Laboratory of Kidney Diseases,National Clinical Research Center for Kidney Diseases,Beijing Key Laboratory of Kidney Disease Research,Beijing 100853,China [3]Department of Anesthesiology,The First Affiliated Hospital,Jinzhou Medical University,Jinzhou,Liaoning 121000,China [4]Department of Burn and Plastic Surgery,The Fourth Medical Center of Chinese PLA General Hospital,Beijing 100048,China [5]Department of Anesthesiology,Peking University Third Hospital,Beijing 100191,China [6]Department of Anesthesiology,Chinese PLA General Hospital,Beijing 100853,China [7]Department of Anesthesiology,The First Medical Center of Chinese PLA General Hospital,Beijing 100853,China

出　　处：《Chinese Medical Journal》2024年第21期2603-2614,共12页中华医学杂志(英文版)

基　　金：supported by grants from the National Natural Science Foundation of China(Nos.81970344,82270411,82171464,82003321,and 82100713);the Beijing Hospitals Authority Clinical Medicine Development of Special Funding Support(No.ZYLX202103);the Beijing Hospitals Authority’s Ascent Plan(No.DFL20220203);the China Postdoctoral Science Foundation(No.2021T140791).

摘　　要：Background:Renal ischemia–reperfusion(R-I/R)injury is the most prevalent cause of acute kidney injury,with high mortality and poor prognosis.However,the underlying pathological mechanisms are not yet fully understood.Therefore,this study aimed to investigate the role of N‐myc downstream‐regulated gene 2(Ndrg2)in R-I/R injury.Methods:We examined the expression of Ndrg2 in the kidney under normal physiological conditions and after R-I/R injury by immunofluorescence staining,real-time polymerase chain reaction,and western blotting.We then detected R-I/R injury in Ndrg2-deficient(Ndrg2^(-/-))mice and wild type(Ndrg2+/+)littermates in vivo,and detected oxygen and glucose deprivation and reperfusion(OGD-R)injury in HK-2 cells.We further conducted transcriptomic sequencing to investigate the role of Ndrg2 in R-I/R injury and detected levels of oxidative stress and mitochondrial damage by dihydroethidium staining,biochemical assays,and western blot.Finally,we measured the levels of mitophagy in Ndrg2+/+and Ndrg2^(-/-)mice after R-I/R injury or HK-2 cells in OGD-R injury.Results:Ndrg2 was primarily expressed in renal proximal tubules and its expression was significantly decreased 24 h after R-I/R injury.Ndrg2^(-/-)mice exhibited significantly attenuated R-I/R injury compared to Ndrg2+/+mice.Transcriptomics profiling showed that Ndrg2 deficiency induced perturbations of multiple signaling pathways,downregulated inflammatory responses and oxidative stress,and increased autophagy following R-I/R injury.Further studies revealed that Ndrg2 deficiency reduced oxidative stress and mitochondrial damage.Notably,Ndrg2 deficiency significantly activated phosphatase and tensin homologue on chromosome ten-induced putative kinase 1(PINK1)/Parkin-mediated mitophagy.The downregulation of NDRG2 expression significantly increased cell viability after OGD-R injury,increased the expression of heme oxygenase-1,decreased the expression of nicotinamide adenine dinucleotide phosphate oxidase 4,and increased the expression of the PINK1/Park

关 键 词：Ischemia-reperfusion injury N-myc downstream-regulated gene 2 MITOPHAGY Oxidative stress RENOPROTECTION Oxygen and glucose deprivation 

分 类 号：R73[医药卫生—肿瘤]