Institute of Physiology, Pathophysiology and Toxicology, ZBAF, Witten/Herdecke University, Stockumer Str. 12, 58453, Witten, Germany.
Physiology and Pathophysiology of Cells and Membranes, Medical School OWL, Bielefeld University, Morgenbreede 1, 33615, Bielefeld, Germany.
Arch Toxicol. 2024 Apr;98(4):1043-1059. doi: 10.1007/s00204-023-03677-z. Epub 2024 Jan 30.
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)-induced oxidative stress by targeting ROS/RNS generation or antioxidant defence mechanisms, such as superoxide dismutase (SOD) or HO-metabolizing catalase (CAT). Though ROS/RNS are well-evidenced, the role of distinct ROS profiles in Cd concentration-dependent toxicity is not clear. In renal cells, Cd (10-50 µM) oxidized dihydrorhodamine 123, reaching a maximum at 2-3 h. Increases (up to fourfold) in lipid peroxidation by TBARS assay and HO by Amplex Red were evident within 30 min. ROS and loss in cell viability by MTT assay with 50 µM Cd 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, yet augmented by up to 1.5- and 1.2-fold, respectively, by 10 µM Cd. Moreover, 10 µM, but not 25-50 µM Cd, caused 1.7-fold increase in superoxide anion (O), detected by dihydroethidium, paralled by loss in cell viability, that was abolished by Tempol, MnTBAP, α-tocopherol and SOD1 or CAT overexpression. HO-generating NADPH oxidase 4 (NOX4) was attenuated by 50% with 10 µM Cd at 3 h compared to upregulation by 50 µM Cd (1.4-fold, 30 min), which was sustained for 24 h. In summary, O predominates with low-moderate Cd, driving an adaptive response, whereas oxidative stress by elevated HO at high Cd triggers cell death signaling pathways.Highlights Different levels of reactive oxygen species are generated, depending on cadmium concentration. Superoxide anion predominates and HO is suppressed with low cadmium representing oxidative eustress. High cadmium fosters HO by inhibiting catalase and increasing NOX4 leading to oxidative distress. Superoxide dismutase mimetics and overexpression were less effective with high versus low cadmium. Oxidative stress profile could dictate downstream signalling pathways.
活性氧/氮物质（ROS/RNS）的水平和化学物质决定了氧化应激的适应和不适。肾脏近端小管吸收途径丰富，并且需要大量的氧气用于 ATP 依赖性运输，因此特别容易受到镉（Cd）诱导的氧化应激的影响，这是通过靶向 ROS/RNS 的产生或抗氧化防御机制，如超氧化物歧化酶（SOD）或 HO 代谢过氧化氢酶（CAT）来实现的。尽管 ROS/RNS 已经得到了很好的证实，但在 Cd 浓度依赖性毒性中，不同 ROS 谱的作用尚不清楚。在肾细胞中，Cd（10-50 μM）氧化二氢罗丹明 123，在 2-3 小时达到最大值。TBARS 测定法和 Amplex Red 测定法显示，在 30 分钟内，脂质过氧化和 HO 增加了（高达四倍）。用 50 μM Cd 进行 MTT 测定时，ROS 和细胞活力的损失不能被 SOD 模拟物 Tempol 和 MnTBAP 或 SOD1 过表达完全逆转，而 CAT 表达和 α-生育酚则有效。只有在 6 小时以上 50 μM Cd 的情况下，SOD 和 CAT 活性才会低于对照，但分别被 10 μM Cd 增强了 1.5-和 1.2 倍。此外，只有 10 μM Cd 会引起 1.7 倍的超氧阴离子（O）的增加，这与细胞活力的丧失平行，用 Tempol、MnTBAP、α-生育酚和 SOD1 或 CAT 过表达可以消除这种增加，而 25-50 μM Cd 则不会引起这种增加。HO 生成的 NADPH 氧化酶 4（NOX4）在 3 小时时被 10 μM Cd 降低了约 50%，而在 50 μM Cd 时被上调了约 1.4 倍（30 分钟），这种上调持续了 24 小时。总之，低浓度 Cd 时 O 占主导地位，引发适应性反应，而高浓度 Cd 时 HO 升高引发细胞死亡信号通路。
