title: Regulation of MUTYH, a DNA Repair Enzyme, in Renal Proximal Tubular Epithelial Cells.
abstract: MUTYH is a DNA repair enzyme that initiates a base excision repair (BER) by recognizing and removing 8-Oxoguanine (8-oxoG) and its paired adenine. We demonstrated that both TGF-β1 and H2O2 treatment led to an increased 8-oxoG in cultured human proximal tubule epithelial (HK-2) cells, while the former induced epithelial-mesenchymal transition and the latter caused cell apoptosis. Without stimulation, HK-2 cells showed MUTYH expression in mitochondria. TGF-β1 triggered a transient upregulation of mitochondrial MUTYH and induced the expression of nuclear isoforms, while H2O2 showed no role on MUTYH expression. Ureteral obstruction (UUO) mice exhibited high 8-oxoG reactivity with tubulointerstitial lesions. After obstruction, the MUTYH expression was increased only in tubules at day 3 and decreased with obvious tubular atrophy at day 10. Particularly, MUTYH was primarily located in normal tubular cytoplasm with a dominant mitochondrial form. A few cells with nuclear MUTYH expression were observed in the fibrotic interstitium. We confirmed that increased MUTYH expression was upregulated and positively correlated with the severity of kidney fibrosis. Thus, renal fibrosis caused a cell-type-specific and time-dependent response of oxidative DNA repairs, even within the same tissues. It suggests that intervention of MUTYH might be effective for therapies.
authors.affiliation: Department of Medical Nephrology, Jinling Hospital, Nanjing Clinical School of Southern Medical University, Nanjing 210002, China ; National Clinical Research Center of Kidney Disease, Jinling Hospital, Nanjing University School of Medicine, Nanjing 210002, China.
authors.forename: Jianping
authors.initials: J
authors.lastname: Lu
authors.affiliation: Jiangsu Key Laboratory of Molecular Medicine, School of Medicine, Nanjing University, Nanjing 210093, China.
authors.forename: Xinxiu
authors.initials: X
authors.lastname: Li
authors.affiliation: National Clinical Research Center of Kidney Disease, Jinling Hospital, Nanjing University School of Medicine, Nanjing 210002, China.
authors.forename: Mingcao
authors.initials: M
authors.lastname: Zhang
authors.affiliation: National Clinical Research Center of Kidney Disease, Jinling Hospital, Nanjing University School of Medicine, Nanjing 210002, China.
authors.forename: Zhaohong
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Jiangsu Key Laboratory of Molecular Medicine, School of Medicine, Nanjing University, Nanjing 210093, China.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Wang
authors.affiliation: National Clinical Research Center of Kidney Disease, Jinling Hospital, Nanjing University School of Medicine, Nanjing 210002, China.
authors.forename: Caihong
authors.initials: C
authors.lastname: Zeng
authors.affiliation: Department of Medical Nephrology, Jinling Hospital, Nanjing Clinical School of Southern Medical University, Nanjing 210002, China ; National Clinical Research Center of Kidney Disease, Jinling Hospital, Nanjing University School of Medicine, Nanjing 210002, China.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Liu
authors.affiliation: National Clinical Research Center of Kidney Disease, Jinling Hospital, Nanjing University School of Medicine, Nanjing 210002, China.
authors.forename: Huimei
authors.initials: H
authors.lastname: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D045647:DNA Glycosylases / Q000235:genetics / Q000378:metabolism*; D004272:DNA, Mitochondrial / Q000737:chemistry / Q000378:metabolism; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D006147:Guanine / Q000031:analogs & derivatives / Q000032:analysis / Q000276:immunology; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D007150:Immunohistochemistry; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000166:cytology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D014517:Ureteral Obstruction / Q000378:metabolism / Q000473:pathology
chemical_list: D004272:DNA, Mitochondrial; D053773:Transforming Growth Factor beta1; C024829:8-hydroxyguanine; D006147:Guanine; D006861:Hydrogen Peroxide; D045647:DNA Glycosylases; C061738:mutY adenine glycosylase