title: The mitochondria-targeted antioxidant MitoQ ameliorated tubular injury mediated by mitophagy in diabetic kidney disease via Nrf2/PINK1.
abstract: Mitochondria play a crucial role in tubular injury in diabetic kidney disease (DKD). MitoQ is a mitochondria-targeted antioxidant that exerts protective effects in diabetic mice, but the mechanism underlying these effects is not clear. We demonstrated that mitochondrial abnormalities, such as defective mitophagy, mitochondrial reactive oxygen species (ROS) overexpression and mitochondrial fragmentation, occurred in the tubular cells of db/db mice, accompanied by reduced PINK and Parkin expression and increased apoptosis. These changes were partially reversed following an intraperitoneal injection of mitoQ. High glucose (HG) also induces deficient mitophagy, mitochondrial dysfunction and apoptosis in HK-2 cells, changes that were reversed by mitoQ. Moreover, mitoQ restored the expression, activity and translocation of HG-induced NF-E2-related factor 2 (Nrf2) and inhibited the expression of Kelch-like ECH-associated protein (Keap1), as well as the interaction between Nrf2 and Keap1. The reduced PINK and Parkin expression noted in HK-2 cells subjected to HG exposure was partially restored by mitoQ. This effect was abolished by Nrf2 siRNA and augmented by Keap1 siRNA. Transfection with Nrf2 siRNA or PINK siRNA in HK-2 cells exposed to HG conditions partially blocked the effects of mitoQ on mitophagy and tubular damage. These results suggest that mitoQ exerts beneficial effects on tubular injury in DKD via mitophagy and that mitochondrial quality control is mediated by Nrf2/PINK.
authors.affiliation: Department of Nephrology, 2nd Xiangya Hospital, Central South University, Changsha, Hunan, China. Electronic address: xiaolizndx@163.com.
authors.forename: Li
authors.initials: L
authors.lastname: Xiao
authors.affiliation: Department of Nephrology, 2nd Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Xiaoxuan
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Nephrology, 2nd Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Nephrology, 2nd Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Nephrology, 2nd Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Nephrology, 2nd Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Tang
authors.affiliation: Department of Nephrology, 2nd Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Jiahui
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Nephrology, 2nd Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Qin
authors.affiliation: Department of Nephrology, 2nd Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Nephrology, 2nd Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Chengyuan
authors.initials: C
authors.lastname: Tang
authors.affiliation: Department of Nephrology, 2nd Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Liyu
authors.initials: L
authors.lastname: He
authors.affiliation: Renal Division, Department of Medicine and Glom-NExT Center for Glomerular Kidney Disease and Novel Experimental Therapeutics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Greka
authors.affiliation: Department of Endocrinology and Metabolism, 2nd Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Zhiguang
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Department of Nephrology, 2nd Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Fuyou
authors.initials: F
authors.lastname: Liu
authors.affiliation: Department of Nephrology, 2nd Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Cellular Biology and Anatomy, Augusta University, Augusta, GA, USA.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Dong
authors.affiliation: Department of Nephrology, 2nd Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Sun
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002460:Cell Line; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation; D005947:Glucose / Q000037:antagonists & inhibitors / Q000633:toxicity; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D000072019:Kelch-Like ECH-Associated Protein 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D007684:Kidney Tubules / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D063306:Mitophagy / Q000187:drug effects / Q000235:genetics; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D011494:Protein Kinases / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species; D015398:Signal Transduction; D014451:Ubiquinone / Q000031:analogs & derivatives* / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D000099202:PTEN-Induced Putative Kinase
chemical_list: D000975:Antioxidants; D005947:Glucose; D007004:Hypoglycemic Agents; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; D009943:Organophosphorus Compounds; D011494:Protein Kinases; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D014451:Ubiquinone; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C117301:Keap1 protein, mouse; C495636:Nfe2l2 protein, mouse; C429014:mitoquinone; C111567:parkin protein
keywords: Diabetic kidney disease; Mitophagy; Mitoq; Tubular