Thijssen Sandy, Cuypers Ann, Maringwa John, Smeets Karen, Horemans Nele, Lambrichts Ivo, Van Kerkhove Emmy
Centre for Environmental Sciences, transnationale Universiteit Limburg, School of Life Sciences, Hasselt University, Agoralaan Building D, 3590 Diepenbeek, Belgium.
Toxicology. 2007 Jul 1;236(1-2):29-41. doi: 10.1016/j.tox.2007.03.022. Epub 2007 Mar 31.
Oxidative stress is believed to participate in the early processes of cadmium (Cd)-induced proximal tubular kidney damage. Mice were chronically exposed up to 23 weeks to low Cd concentrations (10 and 100 mg CdCl(2)/l) via the drinking water. Pro- and antioxidant gene expression levels, glutathione, ascorbate and lipid peroxidation levels were measured. Our study provided evidence for an early and a late stress response in the kidney. Metallothioneins were upregulated from 1 week of exposure on and they stayed important during the whole exposure period. After 8 weeks the expression of Bcl2 (anti-apoptotic), Prdx2 and cytosolic superoxide dismutase (Sod1) was reduced in the group exposed to 100 mg CdCl(2)/l, which might indicate a response to Cd-stress. However glutathione, ascorbate and lipid peroxidation levels did not significantly change, and the overall redox balance remained stable. Stable Sod2 transcriptional levels suggested that an increased formation of superoxide anions, which can arise upon Cd-induced mitochondrial free radical generation, was not appearing. A second defence activation was observed after 23 weeks: i.e. an increase of catalase (Cat), glutathione peroxidase 4 (Gpx4) and heme oxygenase 1 (Hmox1), together with NADPH oxidase 4 (Nox4), of which the role has not been studied yet in Cd nephrotoxicity. These findings were in contrast with previous studies, where Cd-induced oxidative stress was detrimental when high Cd concentrations were applied. In conclusion our study provided evidence that a chronic exposure to low Cd concentrations triggered a biphasic defence activation in the kidney that might lead to adaptation and survival.
氧化应激被认为参与了镉（Cd）诱导的近端肾小管损伤的早期过程。通过饮用水使小鼠长期暴露于低镉浓度（10和100 mg CdCl₂/l）环境中长达23周。检测了促氧化和抗氧化基因表达水平、谷胱甘肽、抗坏血酸和脂质过氧化水平。我们的研究为肾脏中的早期和晚期应激反应提供了证据。金属硫蛋白从暴露1周起就上调，并且在整个暴露期间都保持重要作用。8周后，在暴露于100 mg CdCl₂/l的组中，Bcl2（抗凋亡）、Prdx2和胞质超氧化物歧化酶（Sod1）的表达降低，这可能表明对镉应激的一种反应。然而，谷胱甘肽、抗坏血酸和脂质过氧化水平没有显著变化，整体氧化还原平衡保持稳定。稳定的Sod2转录水平表明，由镉诱导的线粒体自由基生成可能产生的超氧阴离子的形成没有增加。在23周后观察到第二次防御激活：即过氧化氢酶（Cat）、谷胱甘肽过氧化物酶4（Gpx4）和血红素加氧酶1（Hmox1）增加，以及NADPH氧化酶4（Nox4）增加，其作用尚未在镉肾毒性中进行研究。这些发现与之前的研究相反，在之前的研究中，当应用高镉浓度时，镉诱导的氧化应激是有害的。总之，我们的研究提供了证据，即长期暴露于低镉浓度会引发肾脏中的双相防御激活，这可能导致适应和存活。
