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Kidney Week

Abstract: TH-PO040

Identification of Anti-Ferroptosis Drugs Functioning as Lipid Peroxyl Radical Scavengers and Its Protective Effect Against AKI

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Mishima, Eikan, Tohoku University Graduate School of Medicine, Sendai, Japan
  • Suzuki, Takehiro, Tohoku University Graduate School of Medicine, Sendai, Japan
  • Ito, Sadayoshi, Katta Hospital, Shiroishi, Japan
  • Abe, Takaaki, Tohoku University Graduate School of Medicine, Sendai, Japan
Background

Ferroptosis, a lipid oxidation-dependent cell death mediated by free radical reactions, is a therapeutic target because of its role in organ damages including acute kidney injury (AKI). Ferroptosis-causing radicals that are targeted by ferroptosis suppressors have not been unequivocally identified. Because certain cytochrome P450 (CYP) substrate drugs can prevent lipid peroxidation via obscure mechanisms, we evaluated their anti-ferroptotic potential and used them to identify ferroptosis-causing radicals.

Methods

We screened of CYP substrate compounds by a cell-based assay to identify drugs with anti-ferroptotic activity, and investigated the mechanism. Radical scavenging activity was evaluated using ESR-spin trapping methods and NBD-Pen, a lipid radical probe that we established. We evaluated the therapeutic potency of the drugs in mouse cisplatin-induced AKI models.

Results

We identified clinically-available various drugs and hormones with anti-ferroptotic properties including rifampicin, promethazine, omeprazole, indole-3-carbinol, carvedilol, propranolol, estradiol, and thyroid hormones. The anti-ferroptotic effects of the drugs were closely associated with the scavenging activity of lipid peroxyl radicals and not much related to interactions with other radicals. The elevated lipid peroxyl radical levels were associated with ferroptosis onset, and known ferroptosis suppressors such as ferrostatin-1 were also lipid peroxyl radical scavengers. The drugs showed anti-ferroptotic effect in various types of cells including tubular cell, podocyte, and renal fibroblast. Moreover, the drugs suppressed tissue lipid peroxidation and ameliorated cisplatin-induced renal injury.

Conclusion

The elevated lipid peroxyl radical would be a trigger for onset of ferroptosis, whereas lipid peroxyl radical scavenging drugs can control ferroptosis-related disorders including AKI.