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

Jiarou Li; Yansong Liu; Jingjing Bai; Tiantian Liu; Xionghai Qin; Tianyou Hu; Sicong Wang; Yunlong Li; Shanpeng Cui; Zhen Quan; Yiming Luo; Junbo Zheng; Hongliang Wang

doi:10.1016/j.ejphar.2023.176194

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

Eur J Pharmacol. 2023 Dec 15:961:176194. doi: 10.1016/j.ejphar.2023.176194. Epub 2023 Nov 23.

Authors

Jiarou Li¹, Yansong Liu¹, Jingjing Bai¹, Tiantian Liu¹, Xionghai Qin², Tianyou Hu¹, Sicong Wang³, Yunlong Li³, Shanpeng Cui¹, Zhen Quan¹, Yiming Luo¹, Junbo Zheng⁴, Hongliang Wang⁵

Affiliations

¹ 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.
² 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.
³ Department of Critical Care Medicine, The Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China.
⁴ Department of Critical Care Medicine, The Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China. Electronic address: icuzhengjunbo@hrbmu.edu.cn.
⁵ Department of Critical Care Medicine, The Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China. Electronic address: icuwanghongliang@hrbmu.edu.cn.

PMID: 38000722
DOI: 10.1016/j.ejphar.2023.176194

Abstract

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.

Keywords: AKI; Ferroptosis; KEAP1-NRF2; Protein binding; Sepsis.

MeSH terms

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

Substances

Kelch-Like ECH-Associated Protein 1
Dexmedetomidine
NF-E2-Related Factor 2
HSP90 Heat-Shock Proteins
KEAP1 protein, human