Mitochondrial Targeted Antioxidant SKQ1 Ameliorates Acute Kidney Injury by Inhibiting Ferroptosis.

Abstract

Emerging evidence suggests that ferroptosis is highly correlated with the pathogenesis of acute kidney injury (AKI). Ferroptosis, an iron-dependent form of cell death, is manifested by a toxic accumulation of lipid peroxides and ultrastructural changes in mitochondria. We herein investigated the effect of Visomitin (SKQ1), a novel mitochondria-targeting antioxidant, on several AKI models in vivo and in vitro. Our results revealed that SKQ1 treatment greatly reversed renal outcomes in cisplatin, ischemia-reperfusion injury (IRI), or folic acid-induced AKI models. These effects were reflected in attenuated levels of renal injury biomarkers, histologic indices of tubular injury, and inflammatory infiltration in the SKQ1-treated groups. Transcriptomics analysis depicted ferroptosis signaling as the most pronounced pathway downregulated after SKQ1 treatment. Consequently, administration of SKQ1 significantly ameliorated lipid peroxide accumulation and inhibited ferroptosis in the kidneys of mice with AKI. In cultured human proximal tubule epithelial cells (HK2), SKQ1 treatment markedly mitigated cisplatin-induced mitochondrial reactive oxygen species (ROS) production, resulting in lower levels of lipid peroxidation and ferroptosis. In conclusion, SKQ1 treatment protected against ischemic- or nephrotoxic-induced AKI by inhibiting ferroptosis in vivo and in vitro. These results could facilitate a broader understanding of the interaction between mitochondrial antioxidants and ferroptotic defense mechanisms, providing a possible therapeutic strategy in AKI.

• Authors: Jiayu Song, Jingyi Sheng, Juan Lei, Weihua Gan, Yunwen Yang
• Journal: Oxidative medicine and cellular longevity (Oxid Med Cell Longev) Vol. 2022 Pg. 2223957 ( 2022) ISSN: 1942-0994 [Electronic] United States
• PMID: 36193064 (Publication Type: Journal Article)
• Copyright: Copyright © 2022 Jiayu Song et al.

Chemical References

• Antioxidants
• Lipid Peroxides
• Reactive Oxygen Species
• Folic Acid
• Iron
• Cisplatin

Topics

• Acute Kidney Injury (chemically induced, drug therapy, metabolism)
• Animals
• Antioxidants (metabolism)
• Cisplatin (adverse effects)
• Ferroptosis
• Folic Acid (pharmacology)
• Humans
• Iron (metabolism)
• Lipid Peroxides (pharmacology)
• Mice
• Mitochondria (metabolism)
• Reactive Oxygen Species (metabolism)
• Reperfusion Injury (drug therapy, metabolism)