Activation of the Nrf2/ARE signaling pathway ameliorates hyperlipidemia-induced renal tubular epithelial cell injury by inhibiting mtROS-mediated NLRP3 inflammasome activation

• Published in: Frontiers in immunology 2024-04, Vol.15, p.1342350-1342350
• Main Authors: Jiang, Xu-Shun, Liu, Ting, Xia, Yun-Feng, Gan, Hua, Ren, Wei, Du, Xiao-Gang
• Format: Article
• Language: English
• Subjects: Animals; Antioxidant Response Elements; Apoptosis; Cell Line; Disease Models, Animal; Epithelial Cells - metabolism; Humans; hyperlipidemia; Hyperlipidemias - complications; Hyperlipidemias - immunology; Hyperlipidemias - metabolism; Immunology; Inflammasomes - metabolism; Kidney Tubules - metabolism; Kidney Tubules - pathology; Male; Mitochondria - metabolism; mitochondrial ROS; NF-E2-Related Factor 2 - metabolism; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; NLRP3 inflammasome; Nrf2; Rats; Rats, Sprague-Dawley; renal tubular epithelial cells; Signal Transduction
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2024.1342350

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 and , 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.