Mitochondria-derived reactive oxygen species are involved in renal cell ferroptosis during lipopolysaccharide-induced acute kidney injury

• Published in: International immunopharmacology 2022-06, Vol.107, p.108687-108687, Article 108687
• Main Authors: Liang, Nan-Nan, Zhao, Ying, Guo, Yue-Yue, Zhang, Zhi-Hui, Gao, Lan, Yu, De-Xin, Xu, De-Xiang, Xu, Shen
• Format: Article
• Language: English
• Subjects: Acute kidney injury; Antioxidants; Apoptosis; Cell death; Cell size; Chemical compounds; Depletion; Ferroptosis; Kidneys; Lipid peroxidation; Lipids; Lipopolysaccharides; Membrane potential; Mitochondria; Mitochondria-derived reactive oxygen species; Mitochondria-targeted antioxidants; Oxygen; Peroxidation; Pharmacology; Pretreatment; Reactive oxygen species; Renal cortex; Sepsis; Ultrastructure
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2022.108687

•Fer-1 attenuated LPS-induced renal lipid peroxidation, characteristic mitochondrial damage and renal cell death.•Mitochondria-derived ROS contribute, at least partially, to renal cell ferroptosis during LPS-induced AKI.•Mitochondria-targeted antioxidants may be potential therapeutic agents for sepsis-induced AKI. Our earlier studies indicated that reactive oxygen species (ROS) were involved in lipopolysaccharide (LPS)-induced acute kidney injury (AKI). The present study aimed to explore the role of mitochondria-derived ROS on renal cell ferroptosis during LPS-induced AKI. Male CD-1 mice were intraperitoneally injected with LPS (2.0 mg/kg). Renal MDA and 4HNE residue, two markers of lipid peroxidation, were increased in LPS-exposed mice. Oxidized lipids were detected in LPS-treated human HK-2 cells. In vivo, ferroptosis-characteristic ultrastructure changes, including cell volume reduction, nuclear pyknosis and smaller mitochondria, were shown in renal cortex. In vitro, abnormal alteration of mitochondrial membrane potential was observed in LPS-treated human HK-2 cells. Ferrostatin-1, a specific inhibitor of ferroptosis, attenuated LPS-evoked renal lipid peroxidation, ferroptosis-characteristic mitochondrial damage and renal cell death. Mechanistically, mitochondria-derived ROS were elevated in LPS-stimulated HK-2 cells. MitoQ, a mitochondria-targeted antioxidant, almost completely scavenged LPS-stimulated mitochondrial ROS in human HK-2 cells. Moreover, pretreatment with MitoQ attenuated LPS-induced GSH depletion and lipid peroxidation in mouse kidney. Finally, pretreatment with MitoQ alleviated LPS-induced renal cell death and AKI. Taken together, these results suggest that mitochondria-derived ROS contribute, at least partially, to renal cell ferroptosis during LPS-induced AKI. Mitochondria-targeted antioxidants may be potential therapeutic agents for sepsis-induced AKI.