Abstract
Mercury is widely used in industry and has caused global environmental pollution. Inorganic mercury accumulates in the body causes damage to many organs, and the kidney is the most susceptible to the toxic effects of mercury. However, the underlying specific molecular mechanism of renal injury induced by inorganic mercury remains unclear at the cellular level. Therefore, in order to understand its molecular mechanism, we used in vitro method. We established experimental models by treating human embryonic kidney epithelial cell line (HEK-293 T) cells with HgCl2 (0, 1.25, 5, and 20 µmol/L). We found that HgCl2 can lead to a decrease in cell viability and oxidative stress of HEK-293 T, which may be mediated by upregulation mitochondrial fission. In addition, HgCl2 exposure resulted in the mitochondrial disorder of HEK-293 T cells, which was mediated by downregulating the expression of silent information regulator two ortholog 1 (Sirt1)/peroxisome proliferator–activated receptor coactivator-1α (PGC-1α) signaling pathway. In summary, our results suggest that HgCl2 induces HEK-293 T cell toxicity through promoting Sirt1/PGC-1α axis-mediated mitochondrial dynamics disorder and oxidative stress. Sirt1/PGC-1α may be an appealing pharmaceutical target curing HgCl2-induced kidney injury.
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Data Availability
The datasets used or analyzed during the current study are available from the corresponding author on reasonable request.
Abbreviations
- HgCl2 :
-
Mercury dichloride
- HEK-293T:
-
Human embryonic kidney epithelial cell line
- PGC-1α:
-
Peroxisome proliferator-activated receptor coactivator-1α
- Sirt1:
-
Silent information regulator two ortholog 1
- Mfn1:
-
Mitofusin 1
- Mfn2:
-
Mitofusin 2
- Drp1:
-
Dynamin-related protein 1
- ROS:
-
Reactive oxygen species
- ATP:
-
Adenosine-triphosphate
- qRT-PCR:
-
Quantitative real-time PCR
References
Viczek SA, Aldrian A, Pomberger R, Sarc R (2020) Origins and carriers of Sb, As, Cd, Cl, Cr Co, Pb, Hg, and Ni in mixed solid waste-a literature-based evaluation. Waste Manag 103:87–112
Kim KH, Kabir E, Jahan SA (2016) A review on the distribution of Hg in the environment and its human health impacts. J Hazard Mater 306:376–385
Cappelletti S, Piacentino D, Fineschi V, Frati P, D’Errico S, Aromatario M (2019) Mercuric chloride poisoning: symptoms, analysis, therapies, and autoptic findings. A review of the literature. Crit Rev Toxicol 49:329–334
Bridges CC, Zalups RK (2017) The aging kidney and the nephrotoxic effects of mercury. J Toxicol Environ Health B Crit Rev 20:55–80
Jan AT, Azam M, Siddiqui K, Ali A, Choi I, Haq QM (2015) Heavy metals and human health: mechanistic insight into toxicity and counter defense system of antioxidants. Int J Mol Sci 16:29592–29630
Lash LH, Hueni SE, Putt DA, Zalups RK (2005) Role of organic anion and amino acid carriers in transport of inorganic mercury in rat renal basolateral membrane vesicles: influence of compensatory renal growth. Toxicol Sci 88:630–644
Almeer RS, Albasher G, Alotibi F, Alarifi S, Ali D, Alkahtani S (2019) Ziziphus spina-christi leaf extract suppressed mercury chloride-induced nephrotoxicity via Nrf2-antioxidant pathway activation and inhibition of inflammatory and apoptotic signaling. Oxid Med Cell Longev 2019:5634685
Pagliarini DJ, Calvo SE, Chang B, Sheth SA, Vafai SB, Ong SE, Walford GA, Sugiana C, Boneh A, Chen WK, Hill DE, Vidal M, Evans JG, Thorburn DR, Carr SA, Mootha VK (2008) A mitochondrial protein compendium elucidates complex I disease biology. Cell 134:112–123
Friedman JR, Nunnari J (2014) Mitochondrial form and function. Nature 505:335–343
Zhang Z, Li S, Jiang H, Liu B, Lv Z, Guo C, Zhang H (2017) Effects of selenium on apoptosis and abnormal amino acid metabolism induced by excess fatty acid in isolated rat hepatocytes. Mol Nutr Food Res 61:1700016
Kang TC (2020) Nuclear factor-erythroid 2-related factor 2 (Nrf2) and mitochondrial dynamics/mitophagy in neurological diseases. Antioxidants 9:617
Li J, Zheng X, Ma X, Xu X, Du Y, Lv Q, Li X, Wu Y, Sun H, Yu L, Zhang Z (2019) Melatonin protects against chromium(VI)-induced cardiac injury via activating the AMPK/Nrf2 pathway. J Inorg Biochem 197:110698
Yang D, Jiang Y, Wang Y, Lei Q, Zhao X, Yi R, Zhang X (2020) Improvement of flavonoids in lemon seeds on oxidative damage of human embryonic kidney 293T cells induced by H2O2. Oxid Med Cell Longev 2020:3483519
Zulkarnain NN, Anuar N, Johari NA, Sheikh Abdullah SR, Othman AR (2020) Cytotoxicity evaluation of ketoprofen found in pharmaceutical wastewater on HEK 293 cell growth and metabolism. Environ Toxicol Pharmacol 80:103498
Li S, Shi M, Wan Y, Wang Y, Zhu M, Wang B, Zhan Y, Ran B, Wu C (2020) Inflammasome/NF-κB translocation inhibition via PPARγ agonist mitigates inorganic mercury induced nephrotoxicity. Ecotoxicol Environ Saf 201:110801
Han B, Li S, Lv Y, Yang D, Li J, Yang Q, Wu P, Lv Z, Zhang Z (2019) Dietary melatonin attenuates chromium-induced lung injury via activating the Sirt1/Pgc-1 alpha/Nrf2 pathway. Food Funct 10:5555–5565
Lv Y, Jiang H, Li S, Han B, Liu Y, Yang D, Li J, Yang Q, Wu P, Zhang Z (2020) Sulforaphane prevents chromium-induced lung injury in rats via activation of the Akt/GSK-3 beta/Fyn pathway. Environ Pollut 259:113812
Yang Q, Han B, Li S, Wang X, Wu P, Liu Y, Li J, Han B, Deng N, Zhang Z (2021) The link between deacetylation and hepatotoxicity induced by exposure to hexavalent chromium. J Adv Res. https://doi.org/10.1016/j.jare.2021.04.002
Yang D, Yang Q, Fu N, Li S, Han B, Liu Y, Tang Y, Guo X, Lv Z, Zhang Z (2021) Hexavalent chromium induced heart dysfunction via Sesn2-mediated impairment of mitochondrial function and energy supply. Chemosphere 264:128547
Yang D, Tan X, Lv Z, Liu B, Baiyun R, Lu J, Zhang Z (2016) Regulation of Sirt1/Nrf2/TNF-alpha signaling pathway by luteolin is critical to attenuate acute mercuric chloride exposure induced hepatotoxicity. Sci Rep 6:12
Li S, Zheng X, Zhang X, Yu H, Han B, Lv Y, Liu Y, Wang X, Zhang Z (2021) Exploring the liver fibrosis induced by deltamethrin exposure in quails and elucidating the protective mechanism of resveratrol. Ecotoxicol Environ Saf 207:111501
Liu B, Bing Q, Li S, Han B, Lu J, Baiyun R, Zhang X, Lv Y, Wu H, Zhang Z (2019) Role of A(2B) adenosine receptor-dependent adenosine signaling in multi-walled carbon nanotube-triggered lung fibrosis in mice. J Nanobiotechnology 17:45
Wang X, Han B, Wu P, Li S, Lv Y, Lu J, Yang Q, Li J, Zhu Y, Zhang Z (2020) Dibutyl phthalate induces allergic airway inflammation in rats via inhibition of the Nrf2/TSLP/JAK1 pathway. Environ Pollut 267:115564
Li C, Zhang R, Wei H, Wang Y, Chen Y, Zhang H, Li X, Liu H, Li J, Bao J (2021) Enriched environment housing improved the laying hen’s resistance to transport stress via modulating the heat shock protective response and inflammation. Poult Sci 100:100939
Han B, Wang X, Wu P, Jiang H, Yang Q, Li S, Li J, Zhang Z (2021) Pulmonary inflammatory and fibrogenic response induced by graphitized multi-walled carbon nanotube involved in cGAS-STING signaling pathway. J Hazard Mater 417:125984
Yang Q, Han B, Xue J, Lv Y, Li S, Liu Y, Wu P, Wang X, Zhang Z (2020) Hexavalent chromium induces mitochondrial dynamics disorder in rat liver by inhibiting AMPK/PGC-1 alpha signaling pathway. Environ Pollut 265:114855
Zhang Z, Guo C, Jiang H, Han B, Wang X, Li S, Lv Y, Lv Z, Zhu Y (2020) Inflammation response after the cessation of chronic arsenic exposure and post-treatment of natural astaxanthin in liver: potential role of cytokine-mediated cell-cell interactions. Food Funct 11:9252–9262
Lv Y, Bing Q, Lv Z, Xue J, Li S, Han B, Yang Q, Wang X, Zhang Z (2020) Imidacloprid-induced liver fibrosis in quails via activation of the TGF-beta 1/Smad pathway. Sci Total Environ 705:135915
Su Y, Li S, Xin H, Li J, Li X, Zhang R, Li J, Bao J (2020) Proper cold stimulation starting at an earlier age can enhance immunity and improve adaptability to cold stress in broilers. Poult Sci 99:129–141
Li S, Baiyun R, Lv Z, Li J, Han D, Zhao W, Yu L, Deng N, Liu Z, Zhang Z (2019) Exploring the kidney hazard of exposure to mercuric chloride in mice: disorder of mitochondrial dynamics induces oxidative stress and results in apoptosis. Chemosphere 234:822–829
Li S, Jiang H, Han B, Kong T, Lv Y, Yang Q, Wu P, Lv Z, Zhang Z (2020) Dietary luteolin protects against renal anemia in mice. J Funct Foods 65:103740
Caglayan C, Kandemir FM, Darendelioğlu E, Yıldırım S, Kucukler S, Dortbudak MB (2019) Rutin ameliorates mercuric chloride-induced hepatotoxicity in rats via interfering with oxidative stress, inflammation and apoptosis. J Trace Elem Med Biol 56:60–68
Zheng X, Li S, Li J, Lv Y, Wang X, Wu P, Yang Q, Tang Y, Liu Y, Zhang Z (2020) Hexavalent chromium induces renal apoptosis and autophagy via disordering the balance of mitochondrial dynamics in rats. Ecotoxicol Environ Saf 204:111061
Corrêa MG, Bittencourt LO, Nascimento PC, Ferreira RO, Aragão WAB, Silva MCF, Gomes-Leal W, Fernandes MS, Dionizio A, Buzalaf MR, Crespo-Lopez ME, Lima RR (2020) Spinal cord neurodegeneration after inorganic mercury long-term exposure in adult rats: ultrastructural, proteomic and biochemical damages associated with reduced neuronal density. Ecotoxicol Environ Saf 191:110159
Ahmad S, Mahmood R (2019) Mercury chloride toxicity in human erythrocytes: enhanced generation of ROS and RNS, hemoglobin oxidation, impaired antioxidant power, and inhibition of plasma membrane redox system. Environ Sci Pollut Res Int 26:5645–5657
Sudo K, Dao VAN, C, Miyamoto A, Shiraishi M, (2019) Comparative analysis of in vitro neurotoxicity of methylmercury, mercury, cadmium, and hydrogen peroxide on SH-SY5Y cells. J Vet Med Sci 81:828–837
Kiriyama Y, Nochi H (2018) Intra- and intercellular quality control mechanisms of mitochondria. Cells 7:1
Francy CA, Clinton RW, Fröhlich C, Murphy C, Mears JA (2017) Cryo-EM studies of Drp1 reveal cardiolipin interactions that activate the helical oligomer. Sci Rep 7:10744
Li J, Jiang H, Wu P, Li S, Han B, Yang Q, Wang X, Han B, Deng N, Qu B, Zhang Z (2021) Toxicological effects of deltamethrin on quail cerebrum: weakened antioxidant defense and enhanced apoptosis. Environ Pollut 286:117319
Yang D, Han B, Baiyun R, Lv Z, Wang X, Li S, Lv Y, Xue J, Liu Y, Zhang Z (2020) Sulforaphane attenuates hexavalent chromium-induced cardiotoxicity via the activation of the Sesn2/AMPK/Nrf2 signaling pathway. Metallomics 12:2009–2020
Yang L, Zhang Y, Wang F, Luo Z, Guo S, Strähle U (2020) Toxicity of mercury: molecular evidence. Chemosphere 245:125586
Rizwan H, Pal S, Sabnam S, Pal A (2020) High glucose augments ROS generation regulates mitochondrial dysfunction and apoptosis via stress signalling cascades in keratinocytes. Life Sci 241:117148
Puigserver P, Spiegelman BM (2003) Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha): transcriptional coactivator and metabolic regulator. Endocr Rev 24:78–90
Mei Y, Liu B, Su H, Zhang H, Liu F, Ke Q, Sun X, Tan W (2020) Isosteviol sodium protects the cardiomyocyte response associated with the SIRT1/PGC-1 alpha pathway. J Cell Mol Med 24:10866–10875
Soriano FX, Liesa M, Bach D, Chan DC, Palacín M, Zorzano A (2006) Evidence for a mitochondrial regulatory pathway defined by peroxisome proliferator-activated receptor-gamma coactivator-1 alpha, estrogen-related receptor-alpha, and mitofusin 2. Diabetes 55:1783–1791
Karbowski M, Youle RJ (2003) Dynamics of mitochondrial morphology in healthy cells and during apoptosis. Cell Death Differ 10:870–880
Funding
This study was supported by the National Natural Science Foundation of China (31972754).
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BQ Han: Conceptualization, Methodology, Data Curation, Writing–original draft. ZJ Lv: Conceptualization, Methodology, Investigation, Formal analysis. XM Han: Conceptualization, Methodology. SY Li: Conceptualization, Methodology. B Han: Conceptualization, Methodology. QY Yang: Methodology, Validation, Formal analysis. XQ Wang: Software, Formal analysis, Methodology, Data curation. PF Wu: Conceptualization, Investigation. JY Li: Methodology. N Deng: Software, Formal analysis. ZG Zhang: Conceptualization, Methodology, Project administration Writing–Review and Editing, Funding acquisition.
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Han, B., Lv, Z., Han, X. et al. Harmful Effects of Inorganic Mercury Exposure on Kidney Cells: Mitochondrial Dynamics Disorder and Excessive Oxidative Stress. Biol Trace Elem Res 200, 1591–1597 (2022). https://doi.org/10.1007/s12011-021-02766-3
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DOI: https://doi.org/10.1007/s12011-021-02766-3