Myo-inositol oxygenase expression profile modulates pathogenic ferroptosis in the renal proximal tubule

Overexpression of myo-inositol oxygenase (MIOX), a proximal tubular enzyme, exacerbates cellular redox injury in acute kidney injury (AKI). Ferroptosis, a newly coined term associated with lipid hydroperoxidation, plays a critical role in the pathogenesis of AKI. Whether or not MIOX exacerbates tubu...

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Published in:The Journal of clinical investigation Vol. 129; no. 11; pp. 5033 - 5049
Main Authors: Deng, Fei, Sharma, Isha, Dai, Yingbo, Yang, Ming, Kanwar, Yashpal S.
Format: Journal Article
Language:English
Published: United States American Society for Clinical Investigation 01.11.2019
Subjects:
Analysis
Apoptosis
Autophagy
Biochemistry
Biomarkers
Biomedical research
Cancer
Cell death
Cisplatin
Diabetes
DNA damage
Enzymes
Fatty acids
Ferroptosis
Genetic engineering
Glutathione peroxidase
Inositol
Inositol oxygenase
Kidney diseases
Kidneys
Lipid peroxidation
Lipids
Metabolism
NADP
Oxygenase
Pathogenesis
Peroxidase
Physiological aspects
Transgenic mice
United States > US
Nephrology
Apoptosis
ISSN:0021-9738, 1558-8238, 1558-8238
Online Access:Get full text
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Summary:Overexpression of myo-inositol oxygenase (MIOX), a proximal tubular enzyme, exacerbates cellular redox injury in acute kidney injury (AKI). Ferroptosis, a newly coined term associated with lipid hydroperoxidation, plays a critical role in the pathogenesis of AKI. Whether or not MIOX exacerbates tubular damage by accelerating ferroptosis in cisplatin-induced AKI remains elusive. Cisplatin-treated HK-2 cells exhibited notable cell death, which was reduced by ferroptosis inhibitors. Also, alterations in various ferroptosis metabolic sensors, including lipid hydroperoxidation, glutathione peroxidase 4 (GPX4) activity, NADPH and reduced glutathione (GSH) levels, and ferritinophagy, were observed. These perturbations were accentuated by MIOX overexpression, while ameliorated by MIOX knockdown. Likewise, cisplatin-treated CD1 mice exhibited tubular damage and derangement of renal physiological parameters, which were alleviated by ferrostatin-1, a ferroptosis inhibitor. To investigate the relevance of MIOX to ferroptosis, WT mice, MIOX-overexpressing transgenic (MIOX-Tg) mice, and MIOX-KO mice were subjected to cisplatin treatment. In comparison with 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. In conclusion, these findings indicate that ferroptosis, an integral process in the pathogenesis of cisplatin-induced AKI, is modulated by the expression profile of MIOX.
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ISSN:0021-9738
1558-8238
1558-8238
DOI:10.1172/JCI129903