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

• DOI: 10.1091/mbc.e14-01-0044
• Publication Date: 2014-07-09T23:53:26Z
• Authors: Rui Du; Lin Xia; Xiaoxuan Ning; Limin Liu; Wenjuan Sun; Chen Huang; Hanmin Wang; Shiren Sun
• Keywords: Male; Polycomb Repressive Complex 1; 0301 basic medicine; Epithelial-Mesenchymal Transition; Twist-Related Protein 1; Nuclear Proteins; Articles; Hypoxia-Inducible Factor 1, alpha Subunit; Cell Hypoxia; 3. Good health; Rats, Sprague-Dawley; 03 medical and health sciences; Kidney Tubules; Cellular Microenvironment; Gene Expression Regulation; Animals; Humans; RNA, Messenger; Signal Transduction

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.