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

Biological Trace Element Research volume 191, pages 443–452 (2019)Cite this article

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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References

  1. Jarup L, Akesson A (2009) Current status of cadmium as an environmental health problem. Toxicol Appl Pharmacol 238(3):201–208. https://doi.org/10.1016/j.taap.2009.04.020

    Article  CAS  PubMed  Google Scholar 

  2. Rikans LEYT (2000) Mechanisms of cadmium-mediated acute hepatotoxicity. J Biochem Mol Toxicol 14:110–117

    Article  CAS  Google Scholar 

  3. Cuypers A, Plusquin M, Remans T, Jozefczak M, Keunen E, Gielen H, Opdenakker K, Nair AR, Munters E, Artois TJ, Nawrot T, Vangronsveld J, Smeets K (2010) Cadmium stress: an oxidative challenge. Biometals 23(5):927–940. https://doi.org/10.1007/s10534-010-9329-x

    Article  CAS  PubMed  Google Scholar 

  4. Kamiyama T, Miyakawa H, Li JP, Akiba T, Liu JH, Liu J, Marumo F, Sato C (1995) Effects of one-year cadmium exposure on livers and kidneys and their relation to glutathione levels. Res Commun Mol Pathol Pharmacol 88(2):177–186

    CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  6. Kazi TG, Kolachi NF, Afridi HI, Kazi NG, Sirajuddin N, Arain SS (2012) Effects of mineral supplementation on liver cirrhotic/cancer male patients. Biol Trace Elem Res 150(1–3):81–90. https://doi.org/10.1007/s12011-012-9501-y

    Article  CAS  PubMed  Google 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

    Article  CAS  PubMed  Google 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

    Article  CAS  PubMed  Google Scholar 

  9. Zhang CY, Yuan WG, He P, Lei JH, Wang CX (2016) Liver fibrosis and hepatic stellate cells: etiology, pathological hallmarks and therapeutic targets. World J Gastroenterol 22(48):10512–10522. https://doi.org/10.3748/wjg.v22.i48.10512

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Liu X, Xu J, Brenner DA, Kisseleva T (2013) Reversibility of liver fibrosis and inactivation of fibrogenic myofibroblasts. Curr Pathobiol Rep 1(3):209–214. https://doi.org/10.1007/s40139-013-0018-7

    Article  PubMed  PubMed Central  Google 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

    Article  CAS  PubMed  Google Scholar 

  12. del Carmen EM, Souza V, Bucio L, Hernandez E, Damian-Matsumura P, Zaga V, Gutierrez-Ruiz MC (2002) Cadmium induces alpha(1)collagen (I) and metallothionein II gene and alters the antioxidant system in rat hepatic stellate cells. Toxicology 170(1–2):63–73

    Article  Google Scholar 

  13. Souza V, Escobar Mdel C, Bucio L, Hernandez E, Gutierrez-Ruiz MC (2004) Zinc pretreatment prevents hepatic stellate cells from cadmium-produced oxidative damage. Cell Biol Toxicol 20(4):241–251

    Article  CAS  Google Scholar 

  14. Matovic V, Buha A, Ethukic-Cosic D, Bulat Z (2015) Insight into the oxidative stress induced by lead and/or cadmium in blood, liver and kidneys. Food Chem Toxicol 78:130–140. https://doi.org/10.1016/j.fct.2015.02.011

    Article  CAS  PubMed  Google Scholar 

  15. Tsuchida T, Friedman SL (2017) Mechanisms of hepatic stellate cell activation. Nat Rev Gastroenterol Hepatol 14(7):397–411. https://doi.org/10.1038/nrgastro.2017.38

    Article  CAS  Google Scholar 

  16. Forman HJ, Zhang H, Rinna A (2009) Glutathione: overview of its protective roles, measurement, and biosynthesis. Mol Asp Med 30(1–2):1–12. https://doi.org/10.1016/j.mam.2008.08.006

    Article  CAS  Google Scholar 

  17. Lu SC (2013) Glutathione synthesis. Biochim Biophys Acta 1830(5):3143–3153. https://doi.org/10.1016/j.bbagen.2012.09.008

    Article  CAS  PubMed  Google Scholar 

  18. Rana SV, Verma S (1996) Protective effects of GSH, vitamin E, and selenium on lipid peroxidation in cadmium-fed rats. Biol Trace Elem Res 51(2):161–168. https://doi.org/10.1007/bf02785435

    Article  CAS  PubMed  Google Scholar 

  19. Morgan MJ, Liu ZG (2011) Crosstalk of reactive oxygen species and NF-kappaB signaling. Cell Res 21(1):103–115. https://doi.org/10.1038/cr.2010.178

    Article  CAS  PubMed  Google Scholar 

  20. Thevenod F (2009) Cadmium and cellular signaling cascades: to be or not to be? Toxicol Appl Pharmacol 238(3):221–239. https://doi.org/10.1016/j.taap.2009.01.013

    Article  CAS  PubMed  Google Scholar 

  21. Thevenod F, Lee WK (2013) Cadmium and cellular signaling cascades: interactions between cell death and survival pathways. Arch Toxicol 87(10):1743–1786. https://doi.org/10.1007/s00204-013-1110-9

    Article  CAS  PubMed  Google Scholar 

  22. Zhang H, Li L, Wang Y, Dong F, Chen X, Liu F, Xu D, Yi F, Kapron CM, Liu J (2016) NF-kappaB signaling maintains the survival of cadmium-exposed human renal glomerular endothelial cells. Int J Mol Med 38(2):417–422. https://doi.org/10.3892/ijmm.2016.2640

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kim EK, Choi EJ (2015) Compromised MAPK signaling in human diseases: an update. Arch Toxicol 89(6):867–882. https://doi.org/10.1007/s00204-015-1472-2

    Article  CAS  Google Scholar 

  24. Spitzer MH, Nolan GP (2016) Mass cytometry: single cells, many features. Cell 165(4):780–791. https://doi.org/10.1016/j.cell.2016.04.019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Ghatak S, Biswas A, Dhali GK, Chowdhury A, Boyer JL, Santra A (2011) Oxidative stress and hepatic stellate cell activation are key events in arsenic induced liver fibrosis in mice. Toxicol Appl Pharmacol 251(1):59–69. https://doi.org/10.1016/j.taap.2010.11.016

    Article  CAS  PubMed  Google 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

    Article  CAS  PubMed  Google 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

  28. Jaishankar M, Tseten T, Anbalagan N, Mathew BB, Beeregowda KN (2014) Toxicity, mechanism and health effects of some heavy metals. Interdiscip Toxicol 7(2):60–72. https://doi.org/10.2478/intox-2014-0009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Xu MY, Wang P, Sun YJ, Wu YJ (2017) Metabolomic analysis for combined hepatotoxicity of chlorpyrifos and cadmium in rats. Toxicology 384:50–58. https://doi.org/10.1016/j.tox.2017.04.008

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  31. Oyinloye BE, Adenowo AF, Osunsanmi FO, Ogunyinka BI, Nwozo SO, Kappo AP (2016) Aqueous extract of Monodora myristica ameliorates cadmium-induced hepatotoxicity in male rats. SpringerPlus 5:641. https://doi.org/10.1186/s40064-016-2228-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Jumarie C, Fortin C, Houde M, Campbell PG, Denizeau F (2001) Cadmium uptake by Caco-2 cells: effects of Cd complexation by chloride, glutathione, and phytochelatins. Toxicol Appl Pharmacol 170(1):29–38. https://doi.org/10.1006/taap.2000.9075

    Article  CAS  PubMed  Google Scholar 

  33. Jomova K, Valko M (2011) Advances in metal-induced oxidative stress and human disease. Toxicology 283(2–3):65–87. https://doi.org/10.1016/j.tox.2011.03.001

    Article  CAS  PubMed  Google 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

  35. Hu X, Fernandes J, Jones DP, Go YM (2017) Cadmium stimulates myofibroblast differentiation and mouse lung fibrosis. Toxicology 383:50–56. https://doi.org/10.1016/j.tox.2017.03.018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  PubMed  PubMed Central  Google 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

    Article  CAS  PubMed  Google 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Valko M, Jomova K, Rhodes CJ, Kuca K, Musilek K (2016) Redox- and non-redox-metal-induced formation of free radicals and their role in human disease. Arch Toxicol 90(1):1–37. https://doi.org/10.1007/s00204-015-1579-5

    Article  CAS  Google Scholar 

  40. Liu J, Qu W, Kadiiska MB (2009) Role of oxidative stress in cadmium toxicity and carcinogenesis. Toxicol Appl Pharmacol 238(3):209–214. https://doi.org/10.1016/j.taap.2009.01.029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Shukla GS, Hussain T, Srivastava RS, Chandra SV (1989) Glutathione peroxidase and catalase in liver, kidney, testis and brain regions of rats following cadmium exposure and subsequent withdrawal. Ind Health 27(2):59–69

    Article  CAS  Google 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

    Article  CAS  PubMed  Google Scholar 

  43. Olalekan Lawal A, Lawal AF, Ologundudu A, Adeniran OY, Omonkhua A, Obi F (2011) Antioxidant effects of heated garlic juice on cadmium-induced liver damage in rats as compared to ascorbic acid. J Toxicol Sci 36(5):549–557

    Article  Google Scholar 

  44. Zhang C, Lin J, Ge J, Wang LL, Li N, Sun XT, Cao HB, Li JL (2017) Selenium triggers Nrf2-mediated protection against cadmium-induced chicken hepatocyte autophagy and apoptosis. Toxicol in Vitro 44:349–356. https://doi.org/10.1016/j.tiv.2017.07.027

    Article  CAS  PubMed  Google Scholar 

  45. Nemmiche S (2017) Oxidative signaling response to cadmium exposure. Toxicol Sci 156(1):4–10. https://doi.org/10.1093/toxsci/kfw222

    Article  CAS  PubMed  Google Scholar 

  46. Hayden MS, Ghosh S (2012) NF-kappaB, the first quarter-century: remarkable progress and outstanding questions. Genes Dev 26(3):203–234. https://doi.org/10.1101/gad.183434.111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Hart BA, Lee CH, Shukla GS, Shukla A, Osier M, Eneman JD, Chiu JF (1999) Characterization of cadmium-induced apoptosis in rat lung epithelial cells: evidence for the participation of oxidant stress. Toxicology 133(1):43–58

    Article  CAS  Google Scholar 

  48. Chen YR, Tan TH (2000) The c-Jun N-terminal kinase pathway and apoptotic signaling (review). Int J Oncol 16(4):651–662

    CAS  PubMed  Google Scholar 

  49. Davis RJ (2000) Signal transduction by the JNK group of MAP kinases. Cell 103(2):239–252

    Article  CAS  Google 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

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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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Authors and Affiliations

  1. The First Clinical Medical College, Lanzhou University; The Fifth Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, 730000, Gansu, People’s Republic of China

    Longfei Ren, Lei Zhang, Zhongtian Bai, Chenghui Ren, Xianyun Xu, Zeliang Zhang & Xun Li

  2. Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou, 730000, Gansu, People’s Republic of China

    Kuo Qi, Zhongtian Bai & Xun Li

  3. Hepatopancreatobiliary Surgery Institute of Gansu Province, Medical College Cancer Center of Lanzhou University, Lanzhou, 730000, Gansu, People’s Republic of China

    Lei Zhang & Xun Li

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  1. Longfei Ren
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  2. Kuo Qi
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  3. Lei Zhang
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  4. Zhongtian Bai
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  5. Chenghui Ren
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Contributions

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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