title: Hypoxia-induced Bmi1 promotes renal tubular epithelial cell-mesenchymal transition and renal fibrosis via PI3K/Akt signal.
abstract: Hypoxia is an important microenvironmental factor in the development of renal fibrosis; however, the underlying mechanisms are not well elucidated. Here we show that hypoxia induces Bmi1 mRNA and protein expression in human tubular epithelial cells. We further demonstrate that Bmi1 expression might be directly regulated by hypoxia-inducible factor-1a (HIF-1a) under low oxygen. Moreover, chromatin immunoprecipitation and reporter gene assay studies reveal cooperative transactivation of Bmi1 by HIF-1α and Twist. Enforced Bmi1 expression induces epithelial-mesenchymal transition (EMT), whereas silencing endogenous Bmi-1 expression reverses hypoxia-induced EMT. Up-regulation of Bmi1 leads to stabilization of Snail via modulation of PI3K/Akt signaling, whereas ablation of PI3K/Akt signaling partially rescues the phenotype of Bmi1-overexpressing cells, indicating that PI3K/Akt signaling might be a major mediator of Bmi1-induced EMT. In a rat model of obstructive nephropathy, Bmi1 expression increases in a time-dependent manner. Furthermore, we demonstrate that increased levels of Bmi1, correlated with HIF-1α and Twist, are associated with patients with chronic kidney disease. We provide in vitro and in vivo evidence that activation of HIF-1a/Twist-Bmi1 signaling in renal epithelial cells is associated with the development of chronic renal disease and may promote fibrogenesis via modulation of PI3K/Akt/Snail signaling by facilitating EMT.
authors.affiliation: Department of Integrative Oncology and Radiation Oncology, Navy General Hospital, Beijing, 10037 China Department of Nephrology, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Du
authors.affiliation: State Key Laboratory of Cancer Biology and Department of Digestive Diseases, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Xia
authors.affiliation: Department of Geriatrics, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Xiaoxuan
authors.initials: X
authors.lastname: Ning
authors.affiliation: Department of Nephrology, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Limin
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Nephrology, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Sun
authors.affiliation: Department of Nephrology, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Huang
authors.affiliation: Department of Nephrology, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Hanmin
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Nephrology, Fourth Military Medical University, Xi'an 710032, China sunshiren@medmail.com.cn.
authors.forename: Shiren
authors.initials: S
authors.lastname: Sun
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D060833:Cellular Microenvironment; D058750:Epithelial-Mesenchymal Transition; D005786:Gene Expression Regulation; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007684:Kidney Tubules / Q000378:metabolism / Q000473:pathology*; D008297:Male; D009687:Nuclear Proteins / Q000378:metabolism; D063150:Polycomb Repressive Complex 1 / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D051879:Twist-Related Protein 1 / Q000378:metabolism
chemical_list: C069077:BMI1 protein, human; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D012333:RNA, Messenger; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1; D063150:Polycomb Repressive Complex 1