Brd4 inhibition attenuates unilateral ureteral obstruction-induced fibrosis by blocking TGF-β-mediated Nox4 expression.
Brd4 inhibition attenuates unilateral ureteral obstruction-induced fibrosis by blocking TGF-β-mediated Nox4 expression.
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Brd4 抑制通过阻断 TGF-β 介导的 Nox4 表达来减轻单侧输尿管梗阻诱导的纤维化
DOI：
10.1016/j.redox.2016.12.031
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发表时间：
2017-04
期刊：
影响因子：
11.4
通讯作者：
Qin, Zhexue
中科院分区：
文献类型：
--
作者：
Zhou, Baoshang;Mu, Jiao;Gong, Yi;Lu, Caibao;Zhao, Youguang;He, Ting;Qin, Zhexue
发现肾纤维化的新治疗靶点为慢性肾脏疾病的治疗带来了希望。溴结构域和末端外（BET）蛋白抑制剂已显示有效地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，我们确定了用选择性强效化学抑制剂JQ 1抑制BET家族成员Brd 4可以预防肾纤维化的发展，并阻断单侧输尿管梗阻（UUO）大鼠的纤维化进展。用JQ 1或基因敲低抑制Brd 4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，无论是在UUO诱导的纤维化中还是在TGF-β1刺激的HK-2细胞中。Brd 4抑制还抑制体内UUO或HK-2细胞中TGF-β1诱导的氧化应激。此外，在肾细胞中具有组成性活性并参与过氧化氢产生的Nox 4在UUO介导的纤维化过程中上调，并且在HK-2细胞中由TGF-β1诱导，并且这种上调可被Brd 4抑制而减弱。一致地，Nox 4介导的ROS产生和纤维化基因表达在Brd 4抑制后减弱。此外，Nox 4的转录活性被针对Brd 4的JQ 1或siRNA抑制。此外，Smad 3和ERK 1/2磷酸化，这是Nox 4表达的上游信号，在JQ 1给药的UUO大鼠和Brd 4抑制的HK-2细胞中均被抑制。总之，这些结果表明，抑制Brd 4可能通过阻断TGF-β-Nox 4-ROS-纤维化轴来保护肾纤维化，提示Brd 4可能是一个有前途的治疗靶点。Brd 4在肾纤维化过程中表达上调。Brd 4抑制剂JQ 1可预防肾纤维化并延缓纤维化进展。Brd 4抑制通过Nox 4阻断TGF-β1诱导的氧化应激和纤维化。Brd 4通过Smad和ERK途径调节Nox 4的表达。
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. Brd4 was up-regulated in the progression of renal fibrosis. Brd4 inhibitor JQ1 prevented renal fibrosis and delayed the fibrotic progression. Brd4 inhibition blocked TGF-β1-induced oxidative stress and fibrosis through Nox4. Brd4 regulated Nox4 expression via Smad and ERK pathways.
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选择性抑制BET溴结构域。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
64.5
作者：
Anand P;Brown JD;Lin CY;Qi J;Zhang R;Artero PC;Alaiti MA;Bullard J;Alazem K;Margulies KB;Cappola TP;Lemieux M;Plutzky J;Bradner JE;Haldar SM
通讯作者：
Haldar SM
影响因子：
4.8
作者：
Kim, Jung-Woong;Jang, Sang-Min;Choi, Kyung-Hee
通讯作者：
Choi, Kyung-Hee
影响因子：
7.4
作者：
Babelova, Andrea;Avaniadi, Despina;Brandes, Ralf P.
通讯作者：
Brandes, Ralf P.
DOI：
10.1152/ajplung.00090.2010
发表时间：
2010-10-01
影响因子：
4.9
作者：
Lu, Xianghuai;Murphy, Tamara C.;Hart, C. Michael
通讯作者：
Hart, C. Michael