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Open AccessArticle

Radiocontrast Agent Diatrizoic Acid Induces Mitophagy and Oxidative Stress via Calcium Dysregulation

Department of Biomedical Sciences, Toxicology Research Cluster, Joan C. Edwards School of Medicine, Marshall University, 1 Marshall Drive, Huntington, WV 25755, USA
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Int. J. Mol. Sci. 2019, 20(17), 4074; https://doi.org/10.3390/ijms20174074
Received: 20 May 2019 / Revised: 17 August 2019 / Accepted: 18 August 2019 / Published: 21 August 2019
(This article belongs to the Special Issue Nephrotoxicity 2019)
Contrast-induced acute kidney injury (CI-AKI) is the third most common cause of hospital associated kidney damage. Potential mechanisms of CI-AKI may involve diminished renal hemodynamics, inflammatory responses, and direct cytotoxicity. The hypothesis for this study is that diatrizoic acid (DA) induces direct cytotoxicity to human proximal tubule (HK-2) cells via calcium dysregulation, mitochondrial dysfunction, and oxidative stress. HK-2 cells were exposed to 0–30 mg I/mL DA or vehicle for 2–24 h. Conversion of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and trypan blue exclusion indicated a decrease in mitochondrial and cell viability within 2 and 24 h, respectively. Mitochondrial dysfunction was apparent within 8 h post exposure to 15 mg I/mL DA as shown by Seahorse XF cell mito and Glycolysis Stress tests. Mitophagy was increased at 8 h by 15 mg I/mL DA as confirmed by elevated LC3BII/I expression ratio. HK-2 cells pretreated with calcium level modulators BAPTA-AM, EGTA, or 2-aminophenyl borinate abrogated DA-induced mitochondrial damage. DA increased oxidative stress biomarkers of protein carbonylation and 4-hydroxynonenol (4HNE) adduct formation. Caspase 3 and 12 activation was induced by DA compared to vehicle at 24 h. These studies indicate that clinically relevant concentrations of DA impair HK-2 cells by dysregulating calcium, inducing mitochondrial turnover and oxidative stress, and activating apoptosis. View Full-Text
Keywords: contrast-induced acute kidney injury; diatrizoic acid; proximal tubule cytotoxicity; Seahorse XFe; HK-2 cells; mitophagy; oxidative stress contrast-induced acute kidney injury; diatrizoic acid; proximal tubule cytotoxicity; Seahorse XFe; HK-2 cells; mitophagy; oxidative stress
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MDPI and ACS Style

Ward, D.B.; Brown, K.C.; Valentovic, M.A. Radiocontrast Agent Diatrizoic Acid Induces Mitophagy and Oxidative Stress via Calcium Dysregulation. Int. J. Mol. Sci. 2019, 20, 4074.

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