Dexmedetomidine attenuates ferroptosis by Keap1-Nrf2/HO-1 pathway in LPS-induced acute kidney injury.

Autor: Luo RR; Department of Intensive Care Unit, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, 242 Guang-Ji Road, Gusu District, Suzhou, 215008, China.; Suzhou Clinical Medical Center of Critical Care Medicine, Suzhou, 215001, China., Yang J; Department of Nephrology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China., Sun YL; Department of Intensive Care Unit, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, 242 Guang-Ji Road, Gusu District, Suzhou, 215008, China.; Suzhou Clinical Medical Center of Critical Care Medicine, Suzhou, 215001, China., Zhou BY; Department of Intensive Care Unit, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, 242 Guang-Ji Road, Gusu District, Suzhou, 215008, China.; Suzhou Clinical Medical Center of Critical Care Medicine, Suzhou, 215001, China., Zhou SX; Department of Intensive Care Unit, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, 242 Guang-Ji Road, Gusu District, Suzhou, 215008, China.; Suzhou Clinical Medical Center of Critical Care Medicine, Suzhou, 215001, China., Zhang GX; Department of Physiology and Neurosciences, Medical College of Soochow University, 199 Ren-Ai Road, Suzhou Industrial Park, Suzhou, 215123, China. zhangguoxing@suda.edu.cn., Yang AX; Department of Intensive Care Unit, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, 242 Guang-Ji Road, Gusu District, Suzhou, 215008, China. yangax_2000@hotmail.com.; Suzhou Clinical Medical Center of Critical Care Medicine, Suzhou, 215001, China. yangax_2000@hotmail.com.
Jazyk: angličtina
Zdroj: Naunyn-Schmiedeberg's archives of pharmacology [Naunyn Schmiedebergs Arch Pharmacol] 2024 Oct; Vol. 397 (10), pp. 7785-7796. Date of Electronic Publication: 2024 May 09.
DOI: 10.1007/s00210-024-03125-4
Abstrakt: Previous research has demonstrated that Dexmedetomidine (DEX), an α2 adrenergic agonist commonly used for its sedative and analgesic properties, can attenuate lipopolysaccharide (LPS)-induced acute kidney injury (AKI). This study explores the possibility that DEX's protective effects in LPS-induced AKI are mediated through the inhibition of ferroptosis, a form of regulated cell death characterized by iron-dependent lipid peroxidation, and the activation of the antioxidant response through the Keap1/Nrf2/HO-1 signaling pathway. We induced AKI in 42 mice using LPS and divided them into six groups: saline control, LPS, LPS + DEX, LPS + Ferrostatin-1 (LPS + Fer-1; a ferroptosis inhibitor), LPS + DEX with α2-receptor antagonist Altipamizole (LPS + DEX + ATI), and LPS + DEX with Nrf2 inhibitor ML385 (LPS + DEX + ML385). After 24 h, we analyzed blood and kidney tissues. LPS exposure resulted in AKI, with increased serum creatinine, BUN, and cystatin C, and tubular damage, which DEX and Fer-1 ameliorated. However, Altipamizole and ML385 negated these improvements. The LPS group exhibited elevated oxidative stress markers and mitochondrial damage, reduced by DEX and Fer-1, but not when α2-adrenergic or Nrf2 pathways were blocked. Nrf2 and HO-1 expression declined in the LPS group, rebounded with LPS + DEX and LPS + Fer-1, and fell again with inhibitors; inversely, Keap1 expression varied. Our results demonstrate that DEX may protect against LPS-induced AKI, at least partially by regulating ferroptosis and the α2-adrenergic receptor/Keap1/Nrf2/HO-1 pathway, suggesting a potential therapeutic role for DEX in AKI management by modulating cell death and antioxidant defenses.
(© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
Databáze: MEDLINE
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