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

Autor: Li J; Department of Critical Care Medicine, The Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China; Future Medical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China., Liu Y; Department of Critical Care Medicine, The Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China; Future Medical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China., Bai J; Department of Critical Care Medicine, The Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China; Future Medical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China., Liu T; Department of Critical Care Medicine, The Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China; Future Medical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China., Qin X; Future Medical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China; Department of Thoracic Surgery, Harbin Medical University Cancer Hospital, Harbin 150081, China., Hu T; Department of Critical Care Medicine, The Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China; Future Medical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China., Wang S; Department of Critical Care Medicine, The Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China., Li Y; Department of Critical Care Medicine, The Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China., Cui S; Department of Critical Care Medicine, The Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China; Future Medical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China., Quan Z; Department of Critical Care Medicine, The Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China; Future Medical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China., Luo Y; Department of Critical Care Medicine, The Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China; Future Medical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China., Zheng J; Department of Critical Care Medicine, The Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China. Electronic address: icuzhengjunbo@hrbmu.edu.cn., Wang H; Department of Critical Care Medicine, The Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China. Electronic address: icuwanghongliang@hrbmu.edu.cn.
Jazyk: angličtina
Zdroj: European journal of pharmacology [Eur J Pharmacol] 2023 Dec 15; Vol. 961, pp. 176194. Date of Electronic Publication: 2023 Nov 23.
DOI: 10.1016/j.ejphar.2023.176194
Abstrakt: 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.
Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest regarding the publication of this paper.
(Copyright © 2023 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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