Skip to main content
SpringerLink
Log in

Calcium Signaling Involvement in Cadmium-Induced Astrocyte Cytotoxicity and Cell Death Through Activation of MAPK and PI3K/Akt Signaling Pathways

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Cadmium (Cd), a highly ubiquitous toxic heavy metal, can contaminate the environment, including agricultural soil, water and air, via industrial runoff and other sources of pollution. Cd accumulated in the body via direct exposure or through the food chain results in neurodegeneration and many other diseases. Previous studies on its toxicity in the central nervous system (CNS) focused mainly on neurons. To obtain a more comprehensive understanding of Cd toxicity for the CNS, we investigated how astrocytes respond to acute and chronic Cd exposure and its toxic molecular mechanisms. When primary cultures of cerebral cortical astrocytes incubated with 1–300 μM CdCl2, morphological changes, LDH release and cell death were observed in a time and dose-dependent manner. Further studies demonstrated that acute and chronic Cd treatment phosphorylated JNK, p38 and Akt to different degrees, while ERK1/2 was only phosphorylated under low doses of Cd (10 μM) exposure. Inhibition of JNK and PI3K/Akt, but not of p38, could partially protect astrocyte from cytotoxicity in chronic and acute Cd exposure. Moreover, Cd also induced a strong calcium signal, while BAPTA, a specific intracellular calcium (Ca2+) chelator, prevented Cd-induced intracellular increase of calcium levels in astrocytes; inhibited the Cd-induced activation of ERK1/2, JNK, p38 and Akt; and also significantly reduced astrocyte cell death. All of these results suggested that the Cd–Ca2+–MAPK and PI3K/Akt signaling pathways were involved in Cd-induced toxicity in astrocytes. This toxicity involvement indicates that these pathways may be exploited as a target for the prevention of Cd-induced neurodegenerative diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

Abbreviations

Cd:

Cadmium

Ca2+ :

Calcium

CNS:

Central nervous system

AD:

Alzheimer’s disease

PD:

Parkinson’s disease

ALS:

Amyotrophic lateral sclerosis

BBB:

Blood–brain barrier

MAPK:

Mitogen-activated protein kinase

PI3K:

Phosphatidylinositol 3 kinase

p-ERK1/2:

Phosphorylated extracellular regulated kinase

p-JNK:

Phosphorylated c-Jun N-terminal kinase

p-p38:

Phosphorylated p38

p-Akt:

Phosphorylated protein kinase B

FBS:

Fetal bovine serum

References

  1. Choong G, Liu Y, Templeton DM (2014) Interplay of calcium and cadmium in mediating cadmium toxicity. Chem Biol Interact 211:54–65

    Article  CAS  PubMed  Google Scholar 

  2. Mendez-Armenta M, Rios C (2007) Cadmium neurotoxicity. Environ Toxicol Pharmacol 23:350–358

    Article  CAS  PubMed  Google Scholar 

  3. Wang B, Du Y (2013) Cadmium and its neurotoxic effects. Oxid Med Cell Longev 2013:898034

    PubMed Central  PubMed  Google Scholar 

  4. Okuda B, Iwamoto Y, Tachibana H, Sugita M (1997) Parkinsonism after acute cadmium poisoning. Clin Neurol Neurosurg 99:263–265

    Article  CAS  PubMed  Google Scholar 

  5. Du Y, Shang Q (2006) Review of effect on human health for environmental cadmium pollution. Wei Sheng Yan Jiu 35:241–243

    PubMed  Google Scholar 

  6. Waisberg M, Joseph P, Hale B, Beyersmann D (2003) Molecular and cellular mechanisms of cadmium carcinogenesis. Toxicology 192:95–117

    Article  CAS  PubMed  Google Scholar 

  7. Chang YF, Wen JF, Cai JF, Xiao-Ying W, Yang L, Guo YD (2012) An investigation and pathological analysis of two fatal cases of cadmium poisoning. Forensic Sci Int 220:e5–8

    Article  CAS  PubMed  Google Scholar 

  8. Evans J, Hastings L (1992) Accumulation of Cd(II) in the CNS depending on the route of administration: intraperitoneal, intratracheal, or intranasal. Fundam Appl Toxicol 19:275–278

    Article  CAS  PubMed  Google Scholar 

  9. Abbott NJ, Ronnback L, Hansson E (2006) Astrocyte-endothelial interactions at the blood–brain barrier. Nat Rev Neurosci 7:41–53

    Article  CAS  PubMed  Google Scholar 

  10. Tiffany-Castiglioni E, Sierra EM, Wu JN, Rowles TK (1989) Lead toxicity in neuroglia. Neurotoxicology 10:417–443

    CAS  PubMed  Google Scholar 

  11. Li C, Zhao R, Gao K, Wei Z, Yin MY, Lau LT, Chui D, Hoi Yu AC (2011) Astrocytes: implications for neuroinflammatory pathogenesis of Alzheimer’s disease. Curr Alzheimer Res 8:67–80

    Article  PubMed  Google Scholar 

  12. Ransom B, Behar T, Nedergaard M (2003) New roles for astrocytes (stars at last). Trends Neurosci 26:520–522

    Article  CAS  PubMed  Google Scholar 

  13. Liang HJ, Chai RC, Li X, Kong JG, Jiang JH, Ma J, Vatcher G, Yu AC (2015) Astrocytic exportin-7 responds to ischemia through mediating LKB1 translocation from the nucleus to the cytoplasm. J Neurosci Res 93:253–267

    Article  CAS  PubMed  Google Scholar 

  14. Chai RC, Jiang JH, Kwan Wong AY, Jiang F, Gao K, Vatcher G, Hoi Yu AC (2013) AQP5 is differentially regulated in astrocytes during metabolic and traumatic injuries. Glia 61:1748–1765

    Article  PubMed  Google Scholar 

  15. Dong Y, Liu HD, Zhao R, Yang CZ, Chen XQ, Wang XH, Lau LT, Chen J, Yu AC (2009) Ischemia activates JNK/c-Jun/AP-1 pathway to up-regulate 14-3-3gamma in astrocyte. J Neurochem 109(Suppl 1):182–188

    Article  CAS  PubMed  Google Scholar 

  16. Gao K, Wang CR, Jiang F, Wong AY, Su N, Jiang JH, Chai RC, Vatcher G, Teng J, Chen J, Jiang YW, Yu AC (2013) Traumatic scratch injury in astrocytes triggers calcium influx to activate the JNK/c-Jun/AP-1 pathway and switch on GFAP expression. Glia 61:2063–2077

    Article  PubMed  Google Scholar 

  17. Pang Y, Chai CR, Gao K, Jia XH, Kong JG, Chen XQ, Vatcher G, Chen JG, Yu AC (2015) Ischemia preconditioning protects astrocytes from ischemic injury through 14-3-3gamma. J Neurosci Res. doi:10.1002/jnr.23574

    PubMed  Google Scholar 

  18. Chen L, Liu L, Luo Y, Huang S (2008) MAPK and mTOR pathways are involved in cadmium-induced neuronal apoptosis. J Neurochem 105:251–261

    Article  CAS  PubMed  Google Scholar 

  19. Jung YS, Jeong EM, Park EK, Kim YM, Sohn S, Lee SH, Baik EJ, Moon CH (2008) Cadmium induces apoptotic cell death through p38 MAPK in brain microvessel endothelial cells. Eur J Pharmacol 578:11–18

    Article  CAS  PubMed  Google Scholar 

  20. Xu B, Chen S, Luo Y, Chen Z, Liu L, Zhou H, Chen W, Shen T, Han X, Chen L, Huang S (2011) Calcium signaling is involved in cadmium-induced neuronal apoptosis via induction of reactive oxygen species and activation of MAPK/mTOR network. PLoS ONE 6:e19052

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Labudda M (2011) Biochemical mechanisms of neurotoxicity caused by cadmium. Rocz Panstw Zakl Hig 62:357–363

    CAS  PubMed  Google Scholar 

  22. Rigon AP, Cordova FM, Oliveira CS, Posser T, Costa AP, Silva IG, Santos DA, Rossi FM, Rocha JB, Leal RB (2008) Neurotoxicity of cadmium on immature hippocampus and a neuroprotective role for p38 MAPK. Neurotoxicology 29:727–734

    Article  CAS  PubMed  Google Scholar 

  23. Lopez E, Figueroa S, Oset-Gasque MJ, Gonzalez MP (2003) Apoptosis and necrosis: two distinct events induced by cadmium in cortical neurons in culture. Br J Pharmacol 138:901–911

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Yuan Y, Jiang CY, Xu H, Sun Y, Hu FF, Bian JC, Liu XZ, Gu JH, Liu ZP (2013) Cadmium-induced apoptosis in primary rat cerebral cortical neurons culture is mediated by a calcium signaling pathway. PLoS ONE 8:e64330

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Ransom BR, Ransom CB (2012) Astrocytes: multitalented stars of the central nervous system. Methods Mol Biol 814:3–7

    Article  CAS  PubMed  Google Scholar 

  26. Yang CS, Tzou BC, Liu YP, Tsai MJ, Shyue SK, Tzeng SF (2008) Inhibition of cadmium-induced oxidative injury in rat primary astrocytes by the addition of antioxidants and the reduction of intracellular calcium. J Cell Biochem 103:825–834

    Article  CAS  PubMed  Google Scholar 

  27. Rai A, Maurya SK, Khare P, Srivastava A, Bandyopadhyay S (2010) Characterization of developmental neurotoxicity of As, Cd, and Pb mixture: synergistic action of metal mixture in glial and neuronal functions. Toxicol Sci 118:586–601

    Article  CAS  PubMed  Google Scholar 

  28. Gulisano M, Pacini S, Punzi T, Morucci G, Quagliata S, Delfino G, Sarchielli E, Marini M, Vannelli GB (2009) Cadmium modulates proliferation and differentiation of human neuroblasts. J Neurosci Res 87:228–237

    Article  CAS  PubMed  Google Scholar 

  29. Liu J, Kapron CM (2010) Differential induction of MAP kinase signalling pathways by cadmium in primary cultures of mouse embryo limb bud cells. Reprod Toxicol 29:286–291

    Article  CAS  PubMed  Google Scholar 

  30. Escobar Mdel C, Souza V, Bucio L, Hernandez E, Gomez-Quiroz LE, Gutierrez Ruiz MC (2009) MAPK activation is involved in cadmium-induced Hsp70 expression in HepG2 cells. Toxicol Mech Methods 19:503–509

    Article  PubMed  Google Scholar 

  31. Thevenod F (2009) Cadmium and cellular signaling cascades: to be or not to be? Toxicol Appl Pharmacol 238:221–239

    Article  CAS  PubMed  Google Scholar 

  32. Yan Y, Bian JC, Zhong LX, Zhang Y, Sun Y, Liu ZP (2012) Oxidative stress and apoptotic changes of rat cerebral cortical neurons exposed to cadmium in vitro. Biomed Environ Sci 25:172–181

    PubMed  Google Scholar 

  33. Chen L, Xu B, Liu L, Luo Y, Zhou H, Chen W, Shen T, Han X, Kontos CD, Huang S (2011) Cadmium induction of reactive oxygen species activates the mTOR pathway, leading to neuronal cell death. Free Radic Biol Med 50:624–632

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Chen L, Liu L, Huang S (2008) Cadmium activates the mitogen-activated protein kinase (MAPK) pathway via induction of reactive oxygen species and inhibition of protein phosphatases 2A and 5. Free Radic Biol Med 45:1035–1044

    Article  CAS  PubMed  Google Scholar 

  35. Im JY, Paik SG, Han PL (2006) Cadmium-induced astroglial death proceeds via glutathione depletion. J Neurosci Res 83:301–308

    Article  CAS  PubMed  Google Scholar 

  36. Jo C, Koh YH (2013) Cadmium induces N-cadherin cleavage via ERK-mediated gamma-secretase activation in C6 astroglia cells. Toxicol Lett 222:117–121

    Article  CAS  PubMed  Google Scholar 

  37. Lange SC, Bak LK, Waagepetersen HS, Schousboe A, Norenberg MD (2012) Primary cultures of astrocytes: their value in understanding astrocytes in health and disease. Neurochem Res 37:2569–2588

    Article  CAS  PubMed  Google Scholar 

  38. Shen HM, Liu ZG (2006) JNK signaling pathway is a key modulator in cell death mediated by reactive oxygen and nitrogen species. Free Radic Biol Med 40:928–939

    Article  CAS  PubMed  Google Scholar 

  39. Asnaghi L, Bruno P, Priulla M, Nicolin A (2004) mTOR: a protein kinase switching between life and death. Pharmacol Res 50:545–549

    Article  CAS  PubMed  Google Scholar 

  40. Kim EK, Choi EJ (2010) Pathological roles of MAPK signaling pathways in human diseases. Biochim Biophys Acta 1802:396–405

    Article  CAS  PubMed  Google Scholar 

  41. Chen S, Xu Y, Xu B, Guo M, Zhang Z, Liu L, Ma H, Chen Z, Luo Y, Huang S, Chen L (2011) CaMKII is involved in cadmium activation of MAPK and mTOR pathways leading to neuronal cell death. J Neurochem 119:1108–1118

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  42. Yuan Y, Jiang C, Hu F, Wang Q, Zhang K, Wang Y, Gu J, Liu X, Bian J, Liu Z (2015) The role of mitogen-activated protein kinase in cadmium-induced primary rat cerebral cortical neurons apoptosis via a mitochondrial apoptotic pathway. J Trace Elem Med Biol 29:275–283

    Article  CAS  PubMed  Google Scholar 

  43. Chen S, Gu C, Xu C, Zhang J, Xu Y, Ren Q, Guo M, Huang S, Chen L (2014) Celastrol prevents cadmium-induced neuronal cell death via targeting JNK and PTEN-Akt/mTOR network. J Neurochem 128:256–266

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  44. Small DH (2009) Dysregulation of calcium homeostasis in Alzheimer’s disease. Neurochem Res 34:1824–1829

    Article  CAS  PubMed  Google Scholar 

  45. Beyersmann D, Hechtenberg S (1997) Cadmium, gene regulation, and cellular signalling in mammalian cells. Toxicol Appl Pharmacol 144:247–261

    Article  CAS  PubMed  Google Scholar 

  46. Marchi B, Burlando B, Panfoli I, Viarengo A (2000) Interference of heavy metal cations with fluorescent Ca2+ probes does not affect Ca2+ measurements in living cells. Cell Calcium 28:225–231

    Article  CAS  PubMed  Google Scholar 

  47. Nishimura Y, Yamaguchi JY, Kanada A, Horimoto K, Kanemaru K, Satoh M, Oyama Y (2006) Increase in intracellular Cd2+ concentration of rat cerebellar granule neurons incubated with cadmium chloride: cadmium cytotoxicity under external Ca(2+)-free condition. Toxicol In Vitro 20:211–216

    Article  CAS  PubMed  Google Scholar 

  48. Malhotra SK, Luong LT, Bhatnagar R, Shnitka TK (1997) Up-regulation of reactive astrogliosis in the rat glioma 9L cell line by combined mechanical and chemical injuries. Cytobios 89:115–134

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the Beijing Natural Science Foundation (7091004), the National Basic Research Program of China (973 program, 2011CB504400), the National Natural Science Foundation of China (81471253, 30870818, 31070974, and 31171009), the Foundation for Innovative Research Groups of the National Natural Science Foundation of China (81221002) to ACHY, and the Foundation of Science and Technology Department of Guizhou Province of China (SY-2014-3024, J-2015-2012) to GG.

Author information

Authors and Affiliations

  1. Neuroscience Research Institute, Key Laboratory for Neuroscience (Ministry of Education) and Key Laboratory for Neuroscience (National Health and Family Planning Commission), Peking University, 38 Xue Yuan Road, Beijing, 100191, China

    Jiao Hua Jiang, Guo Ge, Kai Gao, Ying Pang, Rui Chao Chai, Xi Hua Jia, Jin Ge Kong & Albert Cheung-Hoi Yu

  2. Department of Neurobiology, School of Basic Medical Sciences, Health Science Center, Peking University, Beijing, 100191, China

    Jiao Hua Jiang, Guo Ge, Kai Gao, Ying Pang, Rui Chao Chai, Xi Hua Jia, Jin Ge Kong & Albert Cheung-Hoi Yu

  3. Laboratory of Translational Medicine, Institute of Systems Biomedicine, Peking University, Beijing, 100191, China

    Albert Cheung-Hoi Yu

  4. Department of Human Anatomy, Guizhou Medical University, Guian New Area, Guiyang, 550025, Guizhou, China

    Guo Ge

  5. Hai Kang Life (Beijing) Corporation Ltd., Sino-I Campus No. 1, Beijing Economic-Technological Development Area, Beijing, 100176, China

    Rui Chao Chai & Albert Cheung-Hoi Yu

Authors
  1. Jiao Hua Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Guo Ge
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kai Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ying Pang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Rui Chao Chai
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xi Hua Jia
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jin Ge Kong
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Albert Cheung-Hoi Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Guo Ge or Albert Cheung-Hoi Yu.

Ethics declarations

Conflict of interest

All authors have no conflict of interest.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Figure S1

Phase-contrast microscopy showed FBS may play a protective role when astrocytes are exposed to low level Cd. Phase contrast micrographs of primary cultures of astrocytes in the presence of FBS after low dosages of Cd (0, 1, 2, 5 μM) treatment at day 1, 2, 3, 4 and 5, respectively. Pictures were representative data from at least 3 independent experiments. Bar = 50 μm. (TIFF 16561 kb)

Figure S2

No significant cytotoxicity of the inhibitors alone to astrocytes. LDH release measurements of astrocytes after U0126, SP600125, SB203580, LY294002, BAPTA-AM, SP600125+LY294002 incubation without Cd exposure for 12 h. (TIFF 389 kb)

Figure S3

No significant increase of fluo-3 fluorescent in a Ca 2+ -free medium under 100 µM Cd exposures in astrocytes. Time lapse recordings of calcium levels during 100 μM Cd treatment in primary cultures of astrocytes with the calcium indicator Fluo-3 using a Ca2+-free medium at time points of 0, 15, 30, 45, and 60 min. Bar = 80 μm. (TIFF 2131 kb)

Figure S4

Effect of BAPTA-AM pre-incubation on activation of ERK1/2, JNK, p38 and Akt under Cd treatment in astrocytes. Quantification and statistical analysis of the Western blots results shown in Fig. 7C revealed BAPTA inhibited activation of ERK1/2(A), JNK (B), p38 (C), Akt (D), JNK1(E) and JNK2 (F) with(+)/without(-) Cd treatment (10 μM Cd for 6 h and 100 μM Cd for 1 h) in astrocytes, GAPDH was measured as an internal control. # vs. Cd, ## P<0.01, ### P<0.001, n = 4. (TIFF 3470 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jiang, J.H., Ge, G., Gao, K. et al. Calcium Signaling Involvement in Cadmium-Induced Astrocyte Cytotoxicity and Cell Death Through Activation of MAPK and PI3K/Akt Signaling Pathways. Neurochem Res 40, 1929–1944 (2015). https://doi.org/10.1007/s11064-015-1686-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-015-1686-y

Keywords

Search

Navigation