1. Academic Validation
  2. The epigenetic regulator BRD4 is involved in cadmium-triggered inflammatory response in rat kidney

The epigenetic regulator BRD4 is involved in cadmium-triggered inflammatory response in rat kidney

  • Ecotoxicol Environ Saf. 2021 Aug 13;224:112620. doi: 10.1016/j.ecoenv.2021.112620.
Zhonggui Gong 1 Gang Liu 1 Wenjing Liu 1 Hui Zou 1 Ruilong Song 1 Hongyan Zhao 1 Yan Yuan 1 Jianhong Gu 1 Jianchun Bian 1 Jiaqiao Zhu 2 Zongping Liu 3
Affiliations

Affiliations

  • 1 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.
  • 2 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. Electronic address: zhujiaqiao@yzu.edu.cn.
  • 3 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. Electronic address: liuzongping@yzu.edu.cn.
Abstract

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.

Keywords

BRD4; Cadmium; Inflammatory cytokines; JQ1; Kidney; NF-κB.

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