Pharmacological targeting of BET proteins inhibits renal fibroblast activation and alleviates renal fibrosis
| Autor: | Xiaoxu Zhou, Na Liu, Ting C. Zhao, Monica V. Masucci, Shougang Zhuang, Evelyn Tolbert, Chongxiang Xiong, Xiujuan Zang |
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| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine Nephrology Pathology medicine.medical_treatment Cell Cycle Proteins urologic and male genital diseases Kidney extracellular matrix proteins Pulmonary fibrosis STAT3 biology Nuclear Proteins renal fibrosis 3. Good health G2 Phase Cell Cycle Checkpoints medicine.anatomical_structure unilateral ureteral obstruction Oncology Kidney Diseases RNA Interference bromodomain and extra-terminal proteins Ureteral Obstruction medicine.medical_specialty Heterocyclic Compounds 4 or More Rings Cell Line BET inhibitor 03 medical and health sciences Internal medicine Pathology Section medicine Renal fibrosis Animals Humans business.industry Growth factor Proteins Fibroblasts medicine.disease Fibrosis Research Paper: Pathology Rats Bromodomain Mice Inbred C57BL 030104 developmental biology Cancer research biology.protein I-BET151 business Transcription Factors |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| DOI: | 10.18632/oncotarget.12498 |
| Popis: | // Chongxiang Xiong 1,2 , Monica V. Masucci 2 , Xiaoxu Zhou 2 , Na Liu 1 , Xiujuan Zang 3 , Evelyn Tolbert 2 , Ting C. Zhao 4 and Shougang Zhuang 1,2 1 Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China 2 Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, RI , USA 3 Department of Nephrology, Shanghai Songjiang District Central Hospital, Shanghai, China 4 Department of Surgery, Roger Williams Medical Center, Boston University, Providence, RI, USA Correspondence to: Shougang Zhuang, email: // Keywords : bromodomain and extra-terminal proteins, unilateral ureteral obstruction, renal fibrosis, I-BET151, extracellular matrix proteins, Pathology Section Received : August 02, 2016 Accepted : September 29, 2016 Published : October 06, 2016 Abstract Bromodomain and extra-terminal (BET) protein inhibitors have been shown to effectively inhibit tumorgenesis and ameliorate pulmonary fibrosis by targeting bromodomain proteins that bind acetylated chromatin markers. However, their pharmacological effects in renal fibrosis remain unclear. In this study, we examined the effect of I-BET151, a selective and potent BET inhibitor, on renal fibroblast activation and renal fibrosis. In cultured renal interstitial fibroblasts, exposure of cells to I-BET151, or silencing of bromodoma in-containing protein 4 (Brd4), a key BET protein isoform, significantly reduced their activation as indicated by decreased expression of α-smooth muscle actin, collagen 1 and fibronectin. In a murine model of renal fibrosis induced by unilateral ureteral obstruction (UUO), administration of I-BET151 suppressed the deposition of extracellular matrix proteins, renal fibroblast activation and macrophage infiltration. Mechanistically, I-BET151 treatment abrogated UUO-induced phosphorylation of epidermal growth factor receptor and platelet growth factor receptor-β. It also inhibited the activation of Smad-3, STAT3 and NF-κB pathways, as well as the expression of c-Myc and P53 transcription factors in the kidney. Moreover, BET inhibition resulted in the reduction of renal epithelial cells arrested at the G2/M phase of cell cycle after UUO injury. Finally, injury to the kidney up-regulated Brd4, and I-BET151 treatment abrogated its expression. Brd4 was also highly expressed in human fibrotic kidneys. These data indicate that BET proteins are implicated in the regulation of signaling pathways and transcription factors associated with renal fibrogenesis, and suggest that pharmacological inhibition of BET proteins could be a potential treatment for renal fibrosis. |
| Databáze: | OpenAIRE |
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