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Brd4 inhibition attenuates unilateral ureteral obstruction-induced fibrosis by blocking TGF-β-mediated Nox4 expression.
Redox Biol. 2017 04; 11:390-402.RB

Abstract

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.

Authors+Show Affiliations

Department of Nephrology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.Department of Nephrology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.Department of Nephrology, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.Department of Nephrology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.Department of Urology, Chengdu Military General Hospital, Chengdu 610083, China.Department of Nephrology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.Department of Cardiology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China. Electronic address: zhexueqin@126.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28063381

Citation

Zhou, Baoshang, et al. "Brd4 Inhibition Attenuates Unilateral Ureteral Obstruction-induced Fibrosis By Blocking TGF-β-mediated Nox4 Expression." Redox Biology, vol. 11, 2017, pp. 390-402.
Zhou B, Mu J, Gong Y, et al. Brd4 inhibition attenuates unilateral ureteral obstruction-induced fibrosis by blocking TGF-β-mediated Nox4 expression. Redox Biol. 2017;11:390-402.
Zhou, B., Mu, J., Gong, Y., Lu, C., Zhao, Y., He, T., & Qin, Z. (2017). Brd4 inhibition attenuates unilateral ureteral obstruction-induced fibrosis by blocking TGF-β-mediated Nox4 expression. Redox Biology, 11, 390-402. https://doi.org/10.1016/j.redox.2016.12.031
Zhou B, et al. Brd4 Inhibition Attenuates Unilateral Ureteral Obstruction-induced Fibrosis By Blocking TGF-β-mediated Nox4 Expression. Redox Biol. 2017;11:390-402. PubMed PMID: 28063381.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Brd4 inhibition attenuates unilateral ureteral obstruction-induced fibrosis by blocking TGF-β-mediated Nox4 expression. AU - Zhou,Baoshang, AU - Mu,Jiao, AU - Gong,Yi, AU - Lu,Caibao, AU - Zhao,Youguang, AU - He,Ting, AU - Qin,Zhexue, Y1 - 2016/12/30/ PY - 2016/12/01/received PY - 2016/12/20/revised PY - 2016/12/29/accepted PY - 2017/1/8/pubmed PY - 2017/11/29/medline PY - 2017/1/8/entrez KW - Brd4 KW - Nox4 KW - Renal fibrosis KW - TGF-β1 SP - 390 EP - 402 JF - Redox biology JO - Redox Biol VL - 11 N2 - 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. SN - 2213-2317 UR - https://www.unboundmedicine.com/medline/citation/28063381/Brd4_inhibition_attenuates_unilateral_ureteral_obstruction_induced_fibrosis_by_blocking_TGF_β_mediated_Nox4_expression_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S2213-2317(16)30384-6 DB - PRIME DP - Unbound Medicine ER -