Presentation Authors: Fei Deng*, Changsha, China, People's Republic of, Yingbo Dai, Zhuhai, China, People's Republic of, Isha Sharma, Yashpal S Kanwar, Chicago, IL
Introduction: Myo-inositol oxygenase (MIOX) is specifically expressed in renal tubules, and it accentuates kidney redox injury in cisplatin-induced nephropathy. Ferroptosis, a newly discovered type of cell death, is closely associated with lipid hydroperoxidation, and it plays a significant role in the pathogenesis of acute kidney injury (AKI). Whether or not MIOX exacerbates tubular damage by accelerating ferroptosis in cisplatin-induced AKI needs to be explored.
Methods: CD1 mice, Wild-type (WT) mice, MIOX-overexpressing transgenic (MIOX-TG) mice and MIOX-Null (MIOX-KO) mice were injected with cisplatin to induce acute kidney injury. HK2 cells were also treated with cisplatin in vitro.
Results: Cisplatin-treated HK2 cells exhibited substantial cell death, which was considerably reduced by Fer-1, DFO, and VAD, but not by Nec-1. In addition, various ferroptosis metabolic sensors, including lipid hydroperoxidation, GPX4 activity, NADPH, and ferritinophage, had undergone severe perturbations in cisplatin-treated HK2 cells. These perturbations were further accentuated by MIOX overexpression but ameliorated by MIOX knockdown. In in vivo studies, CD1 mice were subjected to intraperitoneal cisplatin injection with or without Fer-1. Fer-1 substantially decreased the blood creatinine level, and ameliorated renal pathological changes in cisplatin-treated mice. WT mice, MIOX-TG mice and MIOX-KO mice were also injected with cisplatin. In comparison to cisplatin-treated WT mice, cisplatin-treated MIOX-TG mice had more severe renal pathological changes and perturbations in ferroptosis metabolic sensors, which were minimal in cisplatin-treated MIOX-KO mice.
Conclusions: These findings indicate that ferroptosis, an essential part in the pathogenesis of cisplatin-induced nephropathy, is modulated by MIOX.
Source of Funding: NIDDKNational Scince Foundation of China (No. 81470925)