title: Bmi-1 plays a critical role in protection from renal tubulointerstitial injury by maintaining redox balance.
abstract: To determine whether Bmi-1 deficiency could lead to renal tubulointerstitial injury by mitochondrial dysfunction and increased oxidative stress in the kidney, 3-week-old Bmi-1(-/-) mice were treated with the antioxidant N-acetylcysteine (NAC, 1 mg mL(-1) ) in their drinking water, or pyrro-quinoline quinone (PQQ, 4 mg kg(-1) diet) in their diet for 2 weeks, and their renal phenotypes were compared with vehicle-treated Bmi1(-/-) and wild-type mice. Bmi-1 was knocked down in human renal proximal tubular epithelial (HK2) cells which were treated with 1 mm NAC for 72 or 96 h, and their phenotypes were compared with control cells. Five-week-old vehicle-treated Bmi-1(-/-) mice displayed renal interstitial fibrosis, tubular atrophy, and severe renal function impairment with decreased renal cell proliferation, increased renal cell apoptosis and senescence, and inflammatory cell infiltration. Impaired mitochondrial structure, decreased mitochondrial numbers, and increased oxidative stress occurred in Bmi-1(-/-) mice; subsequently, this caused DNA damage, the activation of TGF-β1/Smad signaling, and the imbalance between extracellular matrix synthesis and degradation. Oxidative stress-induced epithelial-to-mesenchymal transition of renal tubular epithelial cells was enhanced in Bmi-1 knocked down HK2 cells. All phenotypic alterations caused by Bmi-1 deficiency were ameliorated by antioxidant treatment. These findings indicate that Bmi-1 plays a critical role in protection from renal tubulointerstitial injury by maintaining redox balance and will be a novel therapeutic target for preventing renal tubulointerstitial injury.
authors.affiliation: The State Key Laboratory of Reproductive Medicine, Department of Anatomy, Histology and Embryology, Nanjing Medical University, Nanjing, China.
authors.forename: Jianliang
authors.initials: J
authors.lastname: Jin
authors.forename: Xianhui
authors.initials: X
authors.lastname: Lv
authors.forename: Lulu
authors.initials: L
authors.lastname: Chen
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Jinbo
authors.initials: J
authors.lastname: Li
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.forename: Rong
authors.initials: R
authors.lastname: Wang
authors.forename: Xiang
authors.initials: X
authors.lastname: Lu
authors.forename: Dengshun
authors.initials: D
authors.lastname: Miao
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004249:DNA Damage; D058750:Epithelial-Mesenchymal Transition; D060005:Genotyping Techniques; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000473:pathology*; D007674:Kidney Diseases / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control*; D048054:Mitogen-Activated Protein Kinase 7 / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D009395:Nephritis, Interstitial; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology
chemical_list: C481581:MAPK7 protein, human; D048054:Mitogen-Activated Protein Kinase 7
keywords: Bmi-1; DNA damage; antioxidant; epithelial-to-mesenchymal transition; oxidative stress; renal tubulointerstitial injury