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Abstract: TH-PO095

Myo-Inositol Oxygenase Promotes Ferroptosis in Cisplatin-Induced AKI

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Deng, Fei, Northwestern University, Chicago, Illinois, United States
  • Sharma, Isha, Northwestern University, Chicago, Illinois, United States
  • Sun, Lin, Second Xiangya Hospital Central South University, Changsha, China
  • Kanwar, Yashpal S., Northwestern University Medical School, Chicago, Illinois, United States
Background

Over-expression of myo-inositol oxygenase (MIOX), a kidney tubular specific enzyme, exacerbates renal redox injury in cisplatin-induced AKI. Recently, a newly coined term, i.e., ferroptosis, has been reported, which is closely associated with lipid peroxidation and it plays a significant role in the pathogenesis of AKI. Whether or not MIOX exacerbates tubular damage by accelerating ferroptosis in cisplatin-induced AKI needs to be investigated.

Methods

CD1 mice were subjected to intraperitoneal cisplatin injection with or without Fer-1, a potent ferroptosis inhibitor. Samples were collected for various studies three days later.

Results

Fer-1 substantially decreased the blood creatinine and urine protein excretion, and ameliorated renal pathological changes in cisplatin-treated mice. Wild-type (WT) mice, MIOX-overexpressing transgenic (MIOX-TG) mice and MIOX-Null (MIOX-KO) mice were injected with cisplatin. In comparison to cisplatin-treated WT mice, MIOX-TG mice had a relatively greater increase in blood creatinine and urine protein excretion, and severe renal pathological changes. These perturbations were minimal in cisplatin-treated MIOX-KO mice. Various ferroptosis metabolic sensors, including lipid peroxidation, GPX4 activity, NADPH, GSH, ferritinophage, mitochondrial deformation and lysosomal permeability, had undergone severe perturbations in MIOX-TG compared to WT mice, and these were not observed in MIOX-KO mice. In vitro studies revealed that cisplatin-induced HK-2 cell death was considerably reduced by Fer-1, DFO (iron cleator), and VAD (apoptosis inhibitor), but not by Nec-1 (necroptosis inhibitor). Also, cisplatin-treated HK-2 cells had severe perturbations in ferroptosis metabolic sensors, which were further accentuated by transfection of MIOX-pcDNA, while ameliorated by MIOX-siRNA.

Conclusion

In conclusion, these findings indicate that ferroptosis, conceivably integral to the pathogenesis of cisplatin-induced AKI, is modulated by the expression of MIOX.

Funding

  • NIDDK Support