Activation of the Nrf2/ARE signaling pathway ameliorates hyperlipidemia-induced renal tubular epithelial cell injury by inhibiting mtROS-mediated NLRP3 inflammasome activation
作者全名：Jiang, Xu-shun; Liu, Ting; Xia, Yun-feng; Gan, Hua; Ren, Wei; Du, Xiao-gang
作者地址：[Jiang, Xu-shun; Xia, Yun-feng; Gan, Hua; Du, Xiao-gang] Chongqing Med Univ, Dept Nephrol, Affiliated Hosp 1, Chongqing, Peoples R China; [Liu, Ting] Chongqing Med Univ, Dept Cardiol, Affiliated Hosp 1, Chongqing 400016, Peoples R China; [Ren, Wei] Chongqing Med Univ, Dept Neurol, Affiliated Hosp 1, Chongqing, Peoples R China; [Du, Xiao-gang] Chongqing Med Univ, Chongqing Key Lab Translat Med Major Metab Dis, Affiliated Hosp 1, Chongqing, Peoples R China
通信作者：Du, XG (通讯作者)，Chongqing Med Univ, Dept Nephrol, Affiliated Hosp 1, Chongqing, Peoples R China.; Ren, W (通讯作者)，Chongqing Med Univ, Dept Neurol, Affiliated Hosp 1, Chongqing, Peoples R China.; Du, XG (通讯作者)，Chongqing Med Univ, Chongqing Key Lab Translat Med Major Metab Dis, Affiliated Hosp 1, Chongqing, Peoples R China.
来源：FRONTIERS IN IMMUNOLOGY
ESI学科分类：IMMUNOLOGY
WOS号：WOS:001215535700001
JCR分区：Q1
影响因子：5.7
年份：2024
卷号：15
期号：
开始页：
结束页：
文献类型：Article
关键词：Nrf2; mitochondrial ROS; NLRP3 inflammasome; hyperlipidemia; renal tubular epithelial cells
摘要：Dyslipidemia is the most prevalent independent risk factor for patients with chronic kidney disease (CKD). Lipid-induced NLRP3 inflammasome activation in kidney-resident cells exacerbates renal injury by causing sterile inflammation. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that modulates the cellular redox balance; however, the exact role of Nrf2 signaling and its regulation of the NLRP3 inflammasome in hyperlipidemia-induced kidney injury are poorly understood. In this study, we demonstrated that activation of the mtROS-NLRP3 inflammasome pathway is a critical contributor to renal tubular epithelial cell (RTEC) apoptosis under hyperlipidemia. In addition, the Nrf2/ARE signaling pathway is activated in renal tubular epithelial cells under hyperlipidemia conditions both in vivo and in vitro, and Nrf2 silencing accelerated palmitic acid (PA)-induced mtROS production, mitochondrial injury, and NLRP3 inflammasome activation. However, the activation of Nrf2 with tBHQ ameliorated mtROS production, mitochondrial injury, NLRP3 inflammasome activation, and cell apoptosis in PA-induced HK-2 cells and in the kidneys of HFD-induced obese rats. Furthermore, mechanistic studies showed that the potential mechanism of Nrf2-induced NLRP3 inflammasome inhibition involved reducing mtROS generation. Taken together, our results demonstrate that the Nrf2/ARE signaling pathway attenuates hyperlipidemia-induced renal injury through its antioxidative and anti-inflammatory effects through the downregulation of mtROS-mediated NLRP3 inflammasome activation.
基金机构：National Natural Science Foundation of China [82200799]; Natural Science Foundation of Chongqing Science and Technology Commission of China [cstc2019jcyj-msxmX0504]; In-hospital Cultivation Fund of the First Affiliated Hospital of Chongqing Medical University [PYJJ2021-11]
基金资助正文：The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study was funded by the National Natural Science Foundation of China (no. 82200799), the Natural Science Foundation of Chongqing Science and Technology Commission of China (no. cstc2019jcyj-msxmX0504), and In-hospital Cultivation Fund of the First Affiliated Hospital of Chongqing Medical University (no. PYJJ2021-11).
