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Abstract/Summary
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<jats:title>Abstract</jats:title><jats:p>Levels and chemical species of reactive oxygen/nitrogen species (ROS/RNS) determine oxidative eustress and distress. Abundance of uptake pathways and high oxygen consumption for ATP-dependent transport makes the renal proximal tubule particularly susceptible to cadmium (Cd<jats:sup>2+</jats:sup>)-induced oxidative stress by targeting ROS/RNS generation or antioxidant defence mechanisms, such as superoxide dismutase (SOD) or H<jats:sub>2</jats:sub>O<jats:sub>2</jats:sub>-metabolizing catalase (CAT). Though ROS/RNS are well-evidenced, the role of distinct ROS profiles in Cd<jats:sup>2+</jats:sup> concentration-dependent toxicity is not clear. In renal cells, Cd<jats:sup>2+</jats:sup> (10–50 µM) oxidized dihydrorhodamine 123, reaching a maximum at 2–3 h. Increases (up to fourfold) in lipid peroxidation by TBARS assay and H<jats:sub>2</jats:sub>O<jats:sub>2</jats:sub> by Amplex Red were evident within 30 min. ROS and loss in cell viability by MTT assay with 50 µM Cd<jats:sup>2+</jats:sup> could not be fully reversed by SOD mimetics Tempol and MnTBAP nor by SOD1 overexpression, whereas CAT expression and α-tocopherol were effective. SOD and CAT activities were attenuated below controls only with >6 h 50 µM Cd<jats:sup>2+</jats:sup>, yet augmented by up to 1.5- and 1.2-fold, respectively, by 10 µM Cd<jats:sup>2+</jats:sup>. Moreover, 10 µM, but not 25–50 µM Cd<jats:sup>2+</jats:sup>, caused 1.7-fold increase in superoxide anion (O<jats:sub>2</jats:sub><jats:sup>•−</jats:sup>), detected by dihydroethidium, paralled by loss in cell viability, that was abolished by Tempol, MnTBAP, α-tocopherol and SOD1 or CAT overexpression. H<jats:sub>2</jats:sub>O<jats:sub>2</jats:sub>-generating NADPH oxidase 4 (NOX4) was attenuated by ~50% with 10 µM Cd<jats:sup>2+</jats:sup> at 3 h compared to upregulation by 50 µM Cd<jats:sup>2+</jats:sup> (~1.4-fold, 30 min), which was sustained for 24 h. In summary, O<jats:sub>2</jats:sub><jats:sup>•−</jats:sup> predominates with low–moderate Cd<jats:sup>2+</jats:sup>, driving an adaptive response, whereas oxidative stress by elevated H<jats:sub>2</jats:sub>O<jats:sub>2</jats:sub> at high Cd<jats:sup>2+</jats:sup> triggers cell death signaling pathways.</jats:p><jats:p>Highlights</jats:p><jats:p><jats:list list-type='bullet'>
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<jats:p>Different levels of reactive oxygen species are generated, depending on cadmium concentration.</jats:p>
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<jats:p>Superoxide anion predominates and H<jats:sub>2</jats:sub>O<jats:sub>2</jats:sub> is suppressed with low cadmium representing oxidative eustress.</jats:p>
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<jats:p>High cadmium fosters H<jats:sub>2</jats:sub>O<jats:sub>2</jats:sub> by inhibiting catalase and increasing NOX4 leading to oxidative distress.</jats:p>
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<jats:p>Superoxide dismutase mimetics and overexpression were less effective with high versus low cadmium.</jats:p>
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<jats:p>Oxidative stress profile could dictate downstream signalling pathways.</jats:p>
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