ETS2 promotes epithelial-to-mesenchymal transition in renal fibrosis by targeting JUNB transcription
Autor: | Qiancheng Song, Bingyi Wu, Xiaochun Bai, Zhenguo Chen, Haibing Lan, Xiaojing Wang, Jun Yang, Xiaolan Ai, Zhong-Kai Cui, Fang Yao |
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Rok vydání: | 2020 |
Předmět: |
Male
0301 basic medicine Epithelial-Mesenchymal Transition JUNB Vimentin Kidney Cell Line Proto-Oncogene Protein c-ets-2 Pathology and Forensic Medicine 03 medical and health sciences 0302 clinical medicine Renal fibrosis Animals Humans Gene silencing Epithelial–mesenchymal transition Molecular Biology Transcription factor biology Chemistry Cell Biology Fibrosis Mice Inbred C57BL 030104 developmental biology 030220 oncology & carcinogenesis Tubulointerstitial fibrosis Cancer research biology.protein Kidney Diseases Chromatin immunoprecipitation Transcription Factors |
Zdroj: | Laboratory Investigation. 100:438-453 |
ISSN: | 0023-6837 |
Popis: | Epithelial-to-mesenchymal transition (EMT) plays an important role in the progression of renal tubulointerstitial fibrosis, a common mechanism leading to end-stage renal failure. V-ets erythroblastosis virus E26 oncogene homolog 2 (ETS2), a transcription factor, exhibits diverse roles in pathogenesis; however, its role in renal fibrosis is not yet fully understood. In this study, we detected the expression of ETS2 in an animal model of renal fibrosis and evaluated the potential role of ETS2 in tubular EMT induced by TGF-β1. We found that ETS2 and profibrogenic factors, alpha-smooth muscle actin (α-SMA) and fibronectin (FN), were significantly increased in the unilateral ureteral obstruction (UUO)-induced renal fibrosis model in mice. In vitro, TGF-β1 induced a high expression of ETS2 dependent on Smad3 and ERK signaling pathway in human proximal tubular epithelial cells (HK2). Knockdown of ETS2 abrogated TGF-β1-mediated expression of profibrogenic factors vimentin, α-SMA, collagen I, and FN in HK2 cells. Mechanistically, ETS2 promoted JUNB expression in HK2 cells after TGF-β1 stimulation. Furthermore, luciferase and Chromatin Immunoprecipitation (ChIP) assays revealed that the binding of ETS2 to three EBS motifs on the promoter of JUNB triggered its transcription. Notably, silencing JUNB reversed the ETS2-induced upregulation of the profibrogenic factors in HK2 cells after TGF-β1 stimulation. These findings suggest that ETS2 mediates TGF-β1-induced EMT in renal tubular cells through JUNB, a novel pathway for preventing renal fibrosis. |
Databáze: | OpenAIRE |
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