Uncovering new therapeutic targets for renal fibrosis holds promise for the treatment of chronic kidney diseases. Bromodomain and extra-terminal (BET) protein inhibitors have been shown to effectively ameliorate pathological fibrotic responses. However, the pharmacological effects and underlying mechanisms of these inhibitors in renal fibrosis remain elusive. In this study, we determined that the inhibition of Brd4, a BET family member, with a selective potent chemical inhibitor, JQ1, could prevent the development of renal fibrosis and block the progression of fibrosis in rats that have undergone unilateral ureteral obstruction (UUO). Inhibiting Brd4 with either JQ1 or genetic knockdown resulted in decreased expression of fibrotic genes such as α-smooth muscle actin, collagen IV and fibronectin both in UUO-induced fibrosis and upon TGF-β1 stimulation in HK-2 cells. Brd4 inhibition also suppressed the oxidative stress induced by UUO in vivo or by TGF-β1 in HK-2 cells. Moreover, Nox4, which is constitutively active in renal cells and is involved in the generation of hydrogen peroxide, was up-regulated during UUO-mediated fibrosis and induced by TGF-β1 in HK-2 cells, and this up-regulation could be blunted by Brd4 inhibition. Consistently, Nox4-mediated ROS generation and fibrotic gene expression were attenuated upon Brd4 inhibition. Further, the transcriptional activity of Nox4 was suppressed by JQ1 or siRNA against Brd4. Additionally, Smad3 and ERK1/2 phosphorylation, which are upstream signals of Nox4 expression, were inhibited both in JQ1-administered UUO rats and Brd4-inhibited HK-2 cells. In conclusion, these results indicated that the inhibition of Brd4 might protect against renal fibrosis by blocking the TGF-β-Nox4-ROS-fibrosis axis, suggesting that Brd4 could be a promising therapeutic target.

译文

发现肾脏纤维化的新治疗靶点有望治疗慢性肾脏疾病。溴结构域和末端外 (BET) 蛋白抑制剂已被证明可以有效改善病理性纤维化反应。然而,这些抑制剂在肾纤维化中的药理作用和潜在机制仍然难以捉摸。在这项研究中,我们确定BET家族成员Brd4与选择性强效化学抑制剂JQ1的抑制作用可以防止发生单侧输尿管梗阻 (UUO) 的大鼠肾脏纤维化的发展并阻断纤维化的进展。在UUO诱导的纤维化和TGF-β1刺激HK-2细胞中,用JQ1或基因敲除抑制Brd4导致纤维化基因如 α-平滑肌肌动蛋白,ⅳ 型胶原和纤连蛋白的表达降低。Brd4抑制也抑制了UUO在体内或TGF-β1在HK-2细胞中诱导的氧化应激。此外,Nox4在肾细胞中具有组成性活性并参与过氧化氢的产生,在UUO介导的纤维化过程中被上调,并由TGF-β1在HK-2细胞中诱导,这种上调可能被Brd4抑制抑制。一致地,Nox4-mediated ROS的产生和纤维化基因表达在Brd4抑制下减弱。此外,针对brd4的JQ1或siRNA抑制了Nox4的转录活性。此外,作为Nox4表达的上游信号的Smad3和ERK1/2磷酸化在JQ1-administered UUO大鼠和Brd4-inhibited HK-2细胞中均被抑制。总之,这些结果表明,Brd4的抑制可能通过阻断tgf-β-nox4-ros纤维化轴来预防肾脏纤维化,这表明Brd4可能是一个有希望的治疗靶标。

+1
+2
100研值 100研值 ¥99课程
检索文献一次
下载文献一次

去下载>

成功解锁2个技能,为你点赞

《SCI写作十大必备语法》
解决你的SCI语法难题!

技能熟练度+1

视频课《玩转文献检索》
让你成为检索达人!

恭喜完成新手挑战

手机微信扫一扫,添加好友领取

免费领《Endnote文献管理工具+教程》

微信扫码, 免费领取

手机登录

获取验证码
登录