Research Papers: Pathology:
Pharmacological targeting of BET proteins inhibits renal fibroblast activation and alleviates renal fibrosis
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Chongxiang Xiong1,2, Monica V. Masucci2, Xiaoxu Zhou2, Na Liu1, Xiujuan Zang3, Evelyn Tolbert2, Ting C. Zhao4 and Shougang Zhuang1,2
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
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
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.
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