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Glutathione Might Attenuate Cadmium-Induced Liver Oxidative Stress and Hepatic Stellate Cell Activation

Abstract

The liver is a major organ involved in cadmium (Cd)-induced oxidative damage. Following liver injury, hepatic stellate cells (HSCs) are activated to participate in the wound healing process, but also facilitate liver fibrosis. Previous studies have observed fibrogenic effects of Cd on liver. However, the oxidative stress mechanisms of Cd-induced HSC activation as well as whether administration of glutathione (GSH) alleviates this activation, remain unclear. In this study, 24 rats were divided randomly into four experimental groups: control, GSH-treated, Cd-treated, and Cd + GSH-treated. After 4 weeks, the liver injury index, HSC-specific activation markers, oxidative stress-related antioxidants, and enzyme activities and signals were measured. Cd uptake and the generation of reactive oxygen species (ROS) in hepatocytes were detected by mass cytometry and fluorescence microscopy, respectively. Levels of aspartate aminotransferase, xanthine oxidase, γ-glutamyl transpeptidase, and α-smooth muscle actin (αSMA) were significantly increased in Cd-treated rats. Activated HSCs positive for αSMA expression and excess collagen deposition were detected in the Cd-treated group. In contrast, activities of the antioxidant enzymes superoxide dismutase, glutathione peroxidase, and catalase were reduced. Supplementation with GSH reversed some of the Cd-induced effects and increased the protein level of phosphorylated (p)-P65 while decreasing p-JNK. Pretreatment with GSH lowered Cd uptake and ROS generation in hepatocytes in vitro. These results indicate that administration of GSH was effective in attenuating Cd-induced oxidative stress via decreasing Cd uptake, restoring the activities of oxidative enzymes, activating NF-κB, inhibiting the JNK signaling pathway, and preventing excessive ROS generation and HSC activation.

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Funding

This study was supported by the grants from the National Natural Science Foundation of China (No. 31570509 and No. 31270543) and research funding of 1st hospital of Lanzhou University (No. ldyyyn2017-23).

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Xun Li, Longfei Ren, and Lei Zhang conceived and designed the experiments; Longfei Ren, Zhongtian Bai, Kuo Qi, Chenghui Ren, Zeliang Zhang, and Xianyun Xu performed research; Longfei Ren and Kuo Qi analyzed the data; Xun Li, Longfei Ren, and Lei Zhang wrote the manuscript. All authors discussed the results and commented the manuscript.

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Correspondence to Xun Li.

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Ren, L., Qi, K., Zhang, L. et al. Glutathione Might Attenuate Cadmium-Induced Liver Oxidative Stress and Hepatic Stellate Cell Activation. Biol Trace Elem Res 191, 443–452 (2019). https://doi.org/10.1007/s12011-019-1641-x

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  • DOI: https://doi.org/10.1007/s12011-019-1641-x

Keywords

  • Cadmium
  • Glutathione
  • Oxidative stress
  • Hepatic stellate cell activation