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

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

Dakota B Ward, Kathleen C Brown, Monica A Valentovic

Int J Mol Sci. 2019 Aug 21;20(17):4074.

PMID: 31438500

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP50978115	Diatrizoic acid		50978-11-5	Price

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