Dexmedetomidine alleviates renal tubular ferroptosis in sepsis-associated AKI by KEAP1 regulating the degradation of GPX4

• Published in: European journal of pharmacology 2023-12, Vol.961, p.176194-176194, Article 176194
• Main Authors: Li, Jiarou, Liu, Yansong, Bai, Jingjing, Liu, Tiantian, Qin, Xionghai, Hu, Tianyou, Wang, Sicong, Li, Yunlong, Cui, Shanpeng, Quan, Zhen, Luo, Yiming, Zheng, Junbo, Wang, Hongliang
• Format: Article
• Language: English
• Subjects: Acute Kidney Injury - drug therapy; Acute Kidney Injury - etiology; Animals; Dexmedetomidine - pharmacology; Dexmedetomidine - therapeutic use; Ferroptosis; HSP90 Heat-Shock Proteins; Humans; Kelch-Like ECH-Associated Protein 1; Male; Mice; Mice, Inbred C57BL; NF-E2-Related Factor 2; Sepsis - complications; Sepsis - drug therapy
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2023.176194

Sepsis-associated acute kidney injury (SA-AKI) has a high mortality rate and lacks effective targeted treatment. We applied lipopolysaccharides-induced injury models in human and mouse renal tubular epithelial cells, and at the same time, we selected a commonly used sedative drug, dexmedetomidine, to investigate its potential for renal protection. We found a significant increase in the expression level of HSP90, and the interaction with glutathione peroxidase 4 (GPX4) led to autophagic degradation of GPX4, triggering ferroptosis. Dexmedetomidine reduced the degradation of GPX4 by increasing the binding of KEAP1 and HSP90 in the cytoplasm. Therefore, lipid peroxidation and ferroptosis were reduced. Similarly, dexmedetomidine showed renal protective effects in C57BL/6J male mice with SA-AKI induced by cecal ligation. Our study reveals a new mechanism of renal tubular epithelial cell ferroptosis in SA-AKI treated with dexmedetomidine.