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

Abstract

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.

• Authors: Nan-Nan Liang, Ying Zhao, Yue-Yue Guo, Zhi-Hui Zhang, Lan Gao, De-Xin Yu, De-Xiang Xu, Shen Xu
• Journal: International immunopharmacology (Int Immunopharmacol) Vol. 107 Pg. 108687 (Jun 2022) ISSN: 1878-1705 [Electronic] Netherlands
• PMID: 35279512 (Publication Type: Journal Article)
• Copyright: Copyright © 2022 Elsevier B.V. All rights reserved.

Chemical References

• Antioxidants
• Lipopolysaccharides
• Reactive Oxygen Species

Topics

• Acute Kidney Injury (drug therapy)
• Animals
• Antioxidants (therapeutic use)
• Female
• Ferroptosis
• Humans
• Kidney (metabolism)
• Lipopolysaccharides (metabolism)
• Male
• Mice
• Mitochondria (metabolism)
• Reactive Oxygen Species (metabolism)