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Hypoxia-induced Bmi1 promotes renal tubular epithelial cell–mesenchymal transition and renal fibrosis via PI3K/Akt signal

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...

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Autores principales: Du, Rui, Xia, Lin, Ning, Xiaoxuan, Liu, Limin, Sun, Wenjuan, Huang, Chen, Wang, Hanmin, Sun, Shiren
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4148254/
https://www.ncbi.nlm.nih.gov/pubmed/25009285
http://dx.doi.org/10.1091/mbc.E14-01-0044
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author Du, Rui
Xia, Lin
Ning, Xiaoxuan
Liu, Limin
Sun, Wenjuan
Huang, Chen
Wang, Hanmin
Sun, Shiren
author_facet Du, Rui
Xia, Lin
Ning, Xiaoxuan
Liu, Limin
Sun, Wenjuan
Huang, Chen
Wang, Hanmin
Sun, Shiren
author_sort Du, Rui
collection PubMed
description 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.
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spelling pubmed-41482542014-11-16 Hypoxia-induced Bmi1 promotes renal tubular epithelial cell–mesenchymal transition and renal fibrosis via PI3K/Akt signal Du, Rui Xia, Lin Ning, Xiaoxuan Liu, Limin Sun, Wenjuan Huang, Chen Wang, Hanmin Sun, Shiren Mol Biol Cell Articles 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. The American Society for Cell Biology 2014-09-01 /pmc/articles/PMC4148254/ /pubmed/25009285 http://dx.doi.org/10.1091/mbc.E14-01-0044 Text en © 2014 Du, Xia, Ning, Liu, et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society of Cell Biology.
spellingShingle Articles
Du, Rui
Xia, Lin
Ning, Xiaoxuan
Liu, Limin
Sun, Wenjuan
Huang, Chen
Wang, Hanmin
Sun, Shiren
Hypoxia-induced Bmi1 promotes renal tubular epithelial cell–mesenchymal transition and renal fibrosis via PI3K/Akt signal
title Hypoxia-induced Bmi1 promotes renal tubular epithelial cell–mesenchymal transition and renal fibrosis via PI3K/Akt signal
title_full Hypoxia-induced Bmi1 promotes renal tubular epithelial cell–mesenchymal transition and renal fibrosis via PI3K/Akt signal
title_fullStr Hypoxia-induced Bmi1 promotes renal tubular epithelial cell–mesenchymal transition and renal fibrosis via PI3K/Akt signal
title_full_unstemmed Hypoxia-induced Bmi1 promotes renal tubular epithelial cell–mesenchymal transition and renal fibrosis via PI3K/Akt signal
title_short Hypoxia-induced Bmi1 promotes renal tubular epithelial cell–mesenchymal transition and renal fibrosis via PI3K/Akt signal
title_sort hypoxia-induced bmi1 promotes renal tubular epithelial cell–mesenchymal transition and renal fibrosis via pi3k/akt signal
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4148254/
https://www.ncbi.nlm.nih.gov/pubmed/25009285
http://dx.doi.org/10.1091/mbc.E14-01-0044
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