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

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) ind...

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Autores principales: Ward, Dakota B., Brown, Kathleen C., Valentovic, Monica A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6747199/
https://www.ncbi.nlm.nih.gov/pubmed/31438500
http://dx.doi.org/10.3390/ijms20174074
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author Ward, Dakota B.
Brown, Kathleen C.
Valentovic, Monica A.
author_facet Ward, Dakota B.
Brown, Kathleen C.
Valentovic, Monica A.
author_sort Ward, Dakota B.
collection PubMed
description 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.
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spelling pubmed-67471992019-09-27 Radiocontrast Agent Diatrizoic Acid Induces Mitophagy and Oxidative Stress via Calcium Dysregulation Ward, Dakota B. Brown, Kathleen C. Valentovic, Monica A. Int J Mol Sci Article 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. MDPI 2019-08-21 /pmc/articles/PMC6747199/ /pubmed/31438500 http://dx.doi.org/10.3390/ijms20174074 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Ward, Dakota B.
Brown, Kathleen C.
Valentovic, Monica A.
Radiocontrast Agent Diatrizoic Acid Induces Mitophagy and Oxidative Stress via Calcium Dysregulation
title Radiocontrast Agent Diatrizoic Acid Induces Mitophagy and Oxidative Stress via Calcium Dysregulation
title_full Radiocontrast Agent Diatrizoic Acid Induces Mitophagy and Oxidative Stress via Calcium Dysregulation
title_fullStr Radiocontrast Agent Diatrizoic Acid Induces Mitophagy and Oxidative Stress via Calcium Dysregulation
title_full_unstemmed Radiocontrast Agent Diatrizoic Acid Induces Mitophagy and Oxidative Stress via Calcium Dysregulation
title_short Radiocontrast Agent Diatrizoic Acid Induces Mitophagy and Oxidative Stress via Calcium Dysregulation
title_sort radiocontrast agent diatrizoic acid induces mitophagy and oxidative stress via calcium dysregulation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6747199/
https://www.ncbi.nlm.nih.gov/pubmed/31438500
http://dx.doi.org/10.3390/ijms20174074
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