Glutathione Might Attenuate Cadmium-Induced Liver Oxidative Stress and Hepatic Stellate Cell Activation
- 28 Downloads
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.
KeywordsCadmium Glutathione Oxidative stress Hepatic stellate cell activation
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.
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).
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
- 5.Baba H, Tsuneyama K, Yazaki M, Nagata K, Minamisaka T, Tsuda T, Nomoto K, Hayashi S, Miwa S, Nakajima T, Nakanishi Y, Aoshima K, Imura J (2013) The liver in itai-itai disease (chronic cadmium poisoning): pathological features and metallothionein expression. Mod Pathol 26(9):1228–1234. https://doi.org/10.1038/modpathol.2013.62 CrossRefPubMedGoogle Scholar
- 7.Kolachi NF, Kazi TG, Afridi HI, Kazi NG, Khan S (2012) Investigation of essential trace and toxic elements in biological samples (blood, serum and scalp hair) of liver cirrhotic/cancer female patients before and after mineral supplementation. Clin Nutr 31(6):967–973. https://doi.org/10.1016/j.clnu.2012.04.015 CrossRefPubMedGoogle Scholar
- 8.Hernandez-Gea V, Friedman SL (2011) Pathogenesis of liver fibrosis. Annu Rev Pathol 6:425–456. https://doi.org/10.1146/annurev-pathol-011110-130246 CrossRefPubMedGoogle Scholar
- 11.El-Mansy AA, Mazroa SA, Hamed WS, Yaseen AH, El-Mohandes EA (2016) Histological and immunohistochemical effects of Curcuma longa on activation of rat hepatic stellate cells after cadmium induced hepatotoxicity. Biotech Histochem 91(3):170–181. https://doi.org/10.3109/10520295.2015.1116048 CrossRefPubMedGoogle Scholar
- 26.Franca MER, Rocha SWS, Oliveira WH, Santos LA, de Oliveira AGV, Barbosa KPS, Nunes AKS, Rodrigues GB, Los DB, Peixoto CA (2018) Diethylcarbamazine attenuates the expression of pro-fibrogenic markers and hepatic stellate cells activation in carbon tetrachloride-induced liver fibrosis. Inflammopharmacology 26(2):599–609. https://doi.org/10.1007/s10787-017-0329-0 CrossRefPubMedGoogle Scholar
- 27.Vomund S, Schafer A, Parnham MJ, Brune B, von Knethen A (2017) Nrf2, the master regulator of anti-oxidative responses. Int J Mol Sci 18(12). https://doi.org/10.3390/ijms18122772
- 30.Zou H, Liu X, Han T, Hu D, Yuan Y, Gu J, Bian J, Liu Z (2015) Alpha-lipoic acid protects against cadmium-induced hepatotoxicity via calcium signalling and gap junctional intercellular communication in rat hepatocytes. J Toxicol Sci 40(4):469–477. https://doi.org/10.2131/jts.40.469 CrossRefPubMedGoogle Scholar
- 34.Prystupa A, Blazewicz A, Kicinski P, Sak JJ, Niedzialek J, Zaluska W (2016) Serum concentrations of selected heavy metals in patients with alcoholic liver cirrhosis from the Lublin Region in Eastern Poland. Int J Environ Res Public Health 13(6). https://doi.org/10.3390/ijerph13060582
- 36.Li FJ, Surolia R, Li H, Wang Z, Liu G, Liu RM, Mirov SB, Athar M, Thannickal VJ, Antony VB (2017) Low dose cadmium exposure induces peribronchiolar fibrosis through site specific phosphorylation of vimentin. Am J Physiol Lung Cell Mol Physiol 313:L80–L91. https://doi.org/10.1152/ajplung.00087.2017 CrossRefPubMedPubMedCentralGoogle Scholar
- 37.Thijssen S, Lambrichts I, Maringwa J, Van Kerkhove E (2007) Changes in expression of fibrotic markers and histopathological alterations in kidneys of mice chronically exposed to low and high Cd doses. Toxicology 238(2–3):200–210. https://doi.org/10.1016/j.tox.2007.06.087 CrossRefPubMedGoogle Scholar
- 38.Cupertino MC, Costa KL, Santos DC, Novaes RD, Condessa SS, Neves AC, Oliveira JA, Matta SL (2013) Long-lasting morphofunctional remodelling of liver parenchyma and stroma after a single exposure to low and moderate doses of cadmium in rats. Int J Exp Pathol 94(5):343–351. https://doi.org/10.1111/iep.12046 CrossRefPubMedPubMedCentralGoogle Scholar
- 42.Jaiswal AK (2004) Nrf2 signaling in coordinated activation of antioxidant gene expression. Free Radic Biol Med 36(10):1199–1207. https://doi.org/10.1016/j.freeradbiomed.2004.02.074 CrossRefPubMedGoogle Scholar
- 50.Chen X, Li J, Cheng Z, Xu Y, Wang X, Li X, Xu D, Kapron CM, Liu J (2016) Low dose cadmium inhibits proliferation of human renal mesangial cells via activation of the JNK pathway. Int J Environ Res Public Health 13(10). https://doi.org/10.3390/ijerph13100990