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Myo-inositol oxygenase expression profile modulates pathogenic ferroptosis in the renal proximal tubule
Fei Deng, … , Ming Yang, Yashpal S. Kanwar
Fei Deng, … , Ming Yang, Yashpal S. Kanwar
Published August 22, 2019
Citation Information: J Clin Invest. 2019;129(11):5033-5049. https://doi.org/10.1172/JCI129903.
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Research Article Nephrology Article has an altmetric score of 3

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

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Abstract

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.

Authors

Fei Deng, Isha Sharma, Yingbo Dai, Ming Yang, Yashpal S. Kanwar

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Figure 4

Cisplatin leads to excessive mitochondrial ROS generation and MIOX overexpression, which in turn accentuates cisplatin-induced lipid hydroperoxidation in HK-2 cells.

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Cisplatin leads to excessive mitochondrial ROS generation and MIOX overe...
Cisplatin treatment increased DHE staining, indicative of mitochondrial ROS, in HK-2 cells, and it was partially reduced by MitoQ treatment (A–D) (n = 6; *P < 0.05 compared with the control group, #P < 0.05 compared with the CP group, 1-way ANOVA with Dunn’s multiple comparisons). Immunoblotting studies revealed increased expression of MIOX following 4 hours of cisplatin treatment (F, left). No obvious MIOX upregulation was observed after 20 hours of cisplatin treatment (F, right). Besides, the status of MIOX overexpression and gene disruption in HK-2 cells was confirmed by immunoblotting studies (F, right; third, fourth, and sixth lanes). Fluorescence microscopy revealed that cisplatin treatment for 20 hours led to increased 4-HNE staining, indicative of lipid hydroperoxidation, in HK-2 cells (E, G, and H) (n = 6; *P < 0.05 compared with the control group, #P < 0.05 compared with the CP group, 1-way ANOVA with Dunn’s multiple comparisons). The hydroperoxidation was accentuated by the overexpression of MIOX while attenuated by MIOX gene disruption (E and I–L). Similar changes in 4-HNE levels in vitro were observed by immunoblotting analyses (F, right). Scale bars: 50 μm.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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