Gong Zhonggui, Liu Gang, Liu Wenjing, Zou Hui, Song Ruilong, Zhao Hongyan, Yuan Yan, Gu Jianhong, Bian Jianchun, Zhu Jiaqiao, Liu Zongping
College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, PR China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, PR China; Jiangsu Key Laboratory of Zoonosis, Yangzhou, PR China.
College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, PR China; Joint International Research Laboratory of Agriculture and Agri-Product Safety of the Ministry of Education of China, Yangzhou University, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, Jiangsu 225009, PR China; Jiangsu Key Laboratory of Zoonosis, Yangzhou, PR China.
Ecotoxicol Environ Saf. 2021 Aug 13;224:112620. doi: 10.1016/j.ecoenv.2021.112620.
Cadmium (Cd) has been described as a potential inflammatory inducer, while increasing evidence shows that inappropriate inflammation is a contributing factor to kidney injury. Hence, research on Cd-triggered inflammatory response is of great significance for elucidating the mechanism of Cd-induced nephrotoxicity. Bromodomain-containing 4 (BRD4) is an important epigenetic regulator involved in the development of many inflammatory diseases, but its regulatory roles in Cd-triggered inflammatory response remain to be clarified. Here, we found that treatment with Cd in Sprague-Dawley rats (2 mg/kg bw, i.p., 5 consecutive days) and in rat kidney cell line (NRK-52E, 0-10 μM, 12 h) induced the transcription of inflammatory cytokines, which could be reduced by JQ1 (BRD4 inhibitor, 25 mg/kg bw, i.p., 3 consecutive days in vivo; 0.5 μM, 12 h in vitro) or BRD4 small interfering RNA (siRNA, in vitro), suggesting that BRD4 participates in Cd-triggered inflammatory response. Next, our study clarified the roles of BRD4 in Cd-triggered inflammatory response. The inhibition of BRD4 decreased Cd-promoted NF-κB nuclear translocation and activation in vivo and in vitro. Cd increased the acetylation level of RelA K310 and enhanced BRD4 binding to acetylated NF-κB RelA in vivo and in vitro, which were abrogated by inhibiting BRD4. In summary, our study suggests that BRD4 is involved in Cd-triggered transcription of inflammatory cytokines by mediating the activation of NF-κB signaling pathway and increasing itself binding to acetylated NF-κB RelA in rat kidney, therefore, BRD4 could be a potential therapeutic target for Cd-induced renal diseases.
镉（Cd）被认为是一种潜在的炎症诱导剂，而越来越多的证据表明，不适当的炎症是导致肾损伤的一个因素。因此，研究镉引发的炎症反应对于阐明镉诱导肾毒性的机制具有重要意义。含溴结构域蛋白4（BRD4）是一种重要的表观遗传调节因子，参与多种炎症性疾病的发展，但其在镉引发的炎症反应中的调节作用仍有待阐明。在此，我们发现，用镉处理Sprague-Dawley大鼠（2毫克/千克体重，腹腔注射，连续5天）和大鼠肾细胞系（NRK-52E，0-10微摩尔，12小时）可诱导炎性细胞因子的转录，而JQ1（BRD4抑制剂，25毫克/千克体重，腹腔注射，体内连续3天；0.5微摩尔，体外12小时）或BRD4小干扰RNA（siRNA，体外）可降低这种转录，这表明BRD4参与了镉引发的炎症反应。接下来，我们的研究阐明了BRD4在镉引发的炎症反应中的作用。抑制BRD4可降低镉在体内和体外促进的NF-κB核转位和激活。镉在体内和体外增加了RelA K310的乙酰化水平，并增强了BRD4与乙酰化NF-κB RelA的结合，而抑制BRD4可消除这种作用。总之，我们的研究表明，BRD4通过介导NF-κB信号通路的激活并增加其自身与大鼠肾脏中乙酰化NF-κB RelA的结合，参与了镉引发的炎性细胞因子转录，因此，BRD4可能是镉诱导的肾脏疾病的一个潜在治疗靶点。
