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.
Highlights
Fibrotic diseases contribute to ∼45% of mortalities in developed countries [1] and represent a significant burden on public health systems
We examined the effect of bromodomains and extra-terminal (BET) protein inhibition on the activation of renal interstitial fibroblasts in cultured rat renal interstitial fibroblasts, as well as the development of renal fibrosis a murine model of renal fibrosis induced by unilateral ureteral obstruction by using I-BET151, a small molecule with potent binding affinity to BRD2, BRD3 and BRD4 [21]
As a first step towards understanding the role of BET protein in renal fibrosis, we examined the effect of I-BET151on renal fibroblast activation in normally cultured renal interstitial fibroblast cells (NRK-49F) with 5% fetal bovine serum (FBS)
Summary
Fibrotic diseases contribute to ∼45% of mortalities in developed countries [1] and represent a significant burden on public health systems. Epigenetics-based therapy has become the focus of scientific investigation This approach www.impactjournals.com/oncotarget involves the use of drugs or other techniques to treat medical conditions by targeting epigenetic mechanisms. Epigenetic regulation affects chromatin dynamics and nucleosome assembly One such modification is histone acetylation which relaxes chromatin structure by loosening their interaction with DNA, thereby facilitating gene expression. A number of smallmolecule inhibitors targeting bromodomain proteins such as JQ1 and I-BET151 have been developed [7,8,9]. These small molecules can bind to bromodomains of BET family proteins and compete with acetylated-lysine histone peptides [10]. The wealth of pre-clinical data supports BET inhibition as a promising new therapeutic strategy against cancer, inflammation and cardiovascular disease [11]
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