Skip to main content

Advertisement

Log in

High Glucose Induces Reactive Oxygen Species-Dependent Matrix Metalloproteinase-9 Expression and Cell Migration in Brain Astrocytes

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

An Erratum to this article was published on 19 April 2013

Abstract

A rising level of glucose has been found in the blood of hyperglycemia and diabetes patients associated with brain inflammatory diseases. These diseases may be due to secretion of proinflammatory mediators by host cells triggered by high concentration of glucose. Moreover, increased plasma levels of matrix metalloproteinases (MMPs), MMP-9 especially, have been observed in patients with brain injuries and may contribute to brain inflammatory diseases. However, whether or not high glucose (HG) level triggers the central nervous system (CNS) inflammatory responses during hyperglycemia and diabetes are still unclear. In this study, we use a transformed astroglial cell (rat brain astrocyte-1; RBA-1) as a model to investigate regulatory mechanisms and roles of MMP-9 induction by HG in these cells. First, we demonstrated that HG upregulated MMP-9 gene expression by gelatin zymography, Western blotting, and reverse transcription-polymerase chain reaction (RT-PCR) analyses. Next, data obtained with selective pharmacological inhibitors and small interfering RNAs (siRNAs) showed that HG-induced MMP-9 expression is mediated through a c-Src-dependent reactive oxygen species (ROS) signal linking to activation of mitogen-activated protein kinases (MAPKs). Subsequently, the transcriptional factor nuclear factor-kappa B (NF-κB) was activated and thereby turned on transcription of MMP-9 gene. Functionally, HG-induced MMP-9 expression enhanced astrocyte migration. These results will provide new insights into the mechanisms of action of HG, supporting the hypothesis that HG may promote brain inflammation and remodeling in development of diabetes and hyperglycemia-induced CNS complications such as neurodegenerative diseases.

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

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Instant access to the full article PDF.

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

Similar content being viewed by others

References

  1. Tomlinson DR, Gardiner NJ (2008) Glucose neurotoxicity. Nat Rev Neurosci 9:36–45

    Article  CAS  PubMed  Google Scholar 

  2. Massengale JL, Gasche Y, Chan PH (2002) Carbohydrate source influences gelatinase production by mouse astrocytes in vitro. Glia 38:240–245

    Article  PubMed  Google Scholar 

  3. Chen J, Cui X, Zacharek A, Cui Y, Roberts C, Chopp M (2011) White matter damage and the effect of matrix metalloproteinases in type 2 diabetic mice after stroke. Stroke 42:445–452

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Llewelyn JG (2003) The diabetic neuropathies: types, diagnosis and management. J Neurol Neurosurg Psychiatry 74(Suppl 2):ii15–ii19

    PubMed  Google Scholar 

  5. Boulton AJ, Drury J, Clarke B, Ward JD (1982) Continuous subcutaneous insulin infusion in the management of painful diabetic neuropathy. Diabetes Care 5:386–390

    Article  CAS  PubMed  Google Scholar 

  6. Archer AG, Watkins PJ, Thomas PK, Sharma AK, Payan J (1983) The natural history of acute painful neuropathy in diabetes mellitus. J Neurol Neurosurg Psychiatry 46:491–499

    Article  CAS  PubMed  Google Scholar 

  7. Bradley JL, Thomas PK, King RH, Muddle JR, Ward JD, Tesfaye S, Boulton AJ, Tsigos C, Young RJ (1995) Myelinated nerve fibre regeneration in diabetic sensory polyneuropathy: correlation with type of diabetes. Acta Neuropathol 90:403–410

    Article  CAS  PubMed  Google Scholar 

  8. Sima AA, Bril V, Nathaniel V, McEwen TA, Brown MB, Lattimer SA, Greene DA (1988) Regeneration and repair of myelinated fibers in sural-nerve biopsy specimens from patients with diabetic neuropathy treated with sorbinil. N Engl J Med 319:548–555

    Article  CAS  PubMed  Google Scholar 

  9. Stamenkovic I (2003) Extracellular matrix remodelling: the role of matrix metalloproteinases. J Pathol 200:448–464

    Article  CAS  PubMed  Google Scholar 

  10. Yong VW, Power C, Forsyth P, Edwards DR (2001) Metalloproteinases in biology and pathology of the nervous system. Nat Rev Neurosci 2:502–511

    Article  CAS  PubMed  Google Scholar 

  11. Lee WJ, Shin CY, Yoo BK, Ryu JR, Choi EY, Cheong JH, Ryu JH, Ko KH (2003) Induction of matrix metalloproteinase-9 (MMP-9) in lipopolysaccharide-stimulated primary astrocytes is mediated by extracellular signal-regulated protein kinase 1/2 (Erk1/2). Glia 41:15–24

    Article  PubMed  Google Scholar 

  12. Chrissobolis S, Faraci FM (2008) The role of oxidative stress and NADPH oxidase in cerebrovascular disease. Trends Mol Med 14:495–502

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Chan PH (2001) Reactive oxygen radicals in signaling and damage in the ischemic brain. J Cereb Blood Flow Metab 21:2–14

    Article  CAS  PubMed  Google Scholar 

  14. Halliwell B (2006) Oxidative stress and neurodegeneration: where are we now? J Neurochem 97:1634–1658

    Article  CAS  PubMed  Google Scholar 

  15. Lewén A, Matz P, Chan PH (2000) Free radical pathways in CNS injury. J Neurotrauma 17:871–890

    Article  PubMed  Google Scholar 

  16. Qin L, Liu Y, Wang T, Wei SJ, Block ML, Wilson B, Liu B, Hong JS (2004) NADPH oxidase mediates lipopolysaccharide-induced neurotoxicity and proinflammatory gene expression in activated microglia. J Biol Chem 279:1415–1421

    Article  CAS  PubMed  Google Scholar 

  17. Wang J, Li G, Wang Z, Zhang X, Yao L, Wang F, Liu S, Yin J, Ling EA, Wang L, Hao A (2012) High glucose-induced expression of inflammatory cytokines and reactive oxygen species in cultured astrocytes. Neuroscience 202:58–68

    Article  CAS  PubMed  Google Scholar 

  18. Wei W, Liu Q, Tan Y, Liu L, Li X, Cai L (2009) Oxidative stress, diabetes, and diabetic complications. Hemoglobin 33:370–377

    Article  CAS  PubMed  Google Scholar 

  19. Shanmugam N, Reddy MA, Guha M, Natarajan R (2003) High glucose-induced expression of proinflammatory cytokine and chemokine genes in monocytic cells. Diabetes 52:1256–1264

    Article  CAS  PubMed  Google Scholar 

  20. Quan Y, Jiang CT, Xue B, Zhu SG, Wang X (2011) High glucose stimulates TNFα and MCP-1 expression in rat microglia via ROS and NF-κB pathways. Acta Pharmacol Sin 32:188–193

    Article  CAS  PubMed  Google Scholar 

  21. Singh P, Jain A, Kaur G (2004) Impact of hypoglycemia and diabetes on CNS: correlation of mitochondrial oxidative stress with DNA damage. Mol Cell Biochem 260:153–159

    Article  CAS  PubMed  Google Scholar 

  22. Nishikawa T, Araki E (2007) Impact of mitochondrial ROS production in the pathogenesis of diabetes mellitus and its complications. Antioxid Redox Signal 9:343–353

    Article  CAS  PubMed  Google Scholar 

  23. Jou TC, Jou MJ, Chen JY, Lee SY (1985) Properties of rat brain astrocytes in long-term culture. Taiwan Yi Xue Hui Za Zhi 84:865–881

    CAS  PubMed  Google Scholar 

  24. Hsieh HL, Yen MH, Jou MJ, Yang CM (2004) Intracellular signalings underlying bradykinin-induced matrix metalloproteinase-9 expression in rat brain astrocyte-1. Cell Signal 16:1163–1176

    Article  CAS  PubMed  Google Scholar 

  25. LeBel CP, Ischiropoulos H, Bondy SC (1992) Evaluation of the probe 2′,7′-dichlorofluorescin as an indicator of reactive oxygen species formation and oxidative stress. Chem Res Toxicol 5:227–231

    Article  CAS  PubMed  Google Scholar 

  26. Bindokas VP, Jordan J, Lee CC, Miller RJ (1996) Superoxide production in rat hippocampal neurons: selective imaging with hydroethidine. J Neurosci 168:1324–1336

    Google Scholar 

  27. Eberhardt W, Schulze M, Engels C, Klasmeier E, Pfeilschifter J (2002) Glucocorticoid-mediated suppression of cytokine-induced matrix metalloproteinase-9 expression in rat mesangial cells: involvement of nuclear factor-κB and Ets transcription factors. Mol Endocrinol 16:1752–1766

    Article  CAS  PubMed  Google Scholar 

  28. Shin MH, Moon YJ, Seo JE, Lee Y, Kim KH, Chung JH (2008) Reactive oxygen species produced by NADPH oxidase, xanthine oxidase, and mitochondrial electron transport system mediate heat shock-induced MMP-1 and MMP-9 expression. Free Radic Biol Med 44:635–645

    Article  CAS  PubMed  Google Scholar 

  29. Wu CY, Hsieh HL, Jou MJ, Yang CM (2004) Involvement of p42/p44 MAPK, p38 MAPK, JNK and nuclear factor-κB in interleukin-1beta-induced matrix metalloproteinase-9 expression in rat brain astrocytes. J Neurochem 90:1477–1488

    Article  CAS  PubMed  Google Scholar 

  30. Haneda M, Araki S, Togawa M, Sugimoto T, Isono M, Kikkawa R (1997) Mitogen-activated protein kinase cascade is activated in glomeruli of diabetic rats and glomerular mesangial cells cultured under high glucose conditions. Diabetes 46:847–853

    Article  CAS  PubMed  Google Scholar 

  31. Liang JL, Xiao DZ, Liu XY, Lin QX, Shan ZX, Zhu JN, Lin SG, Yu XY (2010) High glucose induces apoptosis in AC16 human cardiomyocytes via macrophage migration inhibitory factor and c-Jun N-terminal kinase. Clin Exp Pharmacol Physiol 37:969–973

    Article  CAS  PubMed  Google Scholar 

  32. Rosenberg GA (2002) Matrix metalloproteinases in neuroinflammation. Glia 39:279–291

    Article  PubMed  Google Scholar 

  33. Sanchez AP, Sharma K (2009) Transcription factors in the pathogenesis of diabetic nephropathy. Expert Rev Mol Med 11:e13

    Article  PubMed  Google Scholar 

  34. Chen YW, Chenier I, Chang SY, Tran S, Ingelfinger JR, Zhang SL (2011) High glucose promotes nascent nephron apoptosis via NF-κB and p53 pathways. Am J Physiol Renal Physiol 300:F147–F156

    Article  CAS  PubMed  Google Scholar 

  35. Wrighten SA, Piroli GG, Grillo CA, Reagan LP (2009) A look inside the diabetic brain: contributors to diabetes-induced brain aging. Biochim Biophys Acta 1792:444–453

    Article  CAS  PubMed  Google Scholar 

  36. Baydas G, Reiter RJ, Yasar A, Tuzcu M, Akdemir I, Nedzvetskii VS (2003) Melatonin reduces glial reactivity in the hippocampus, cortex, and cerebellum of streptozotocin-induced diabetic rats. Free Radic Biol Med 35:797–804

    Article  CAS  PubMed  Google Scholar 

  37. Kamata H, Hirata H (1999) Redox regulation of cellular signalling. Cell Signal 11:1–14

    Article  CAS  PubMed  Google Scholar 

  38. Floyd RA (1999) Neuroinflammatory processes are important in neurodegenerative diseases: an hypothesis to explain the increased formation of reactive oxygen and nitrogen species as major factors involved in neurodegenerative disease development. Free Radic Biol Med 26:1346–1355

    Article  CAS  PubMed  Google Scholar 

  39. Infanger DW, Sharma RV, Davisson RL (2006) NADPH oxidases of the brain: distribution, regulation, and function. Antioxid Redox Signal 8:1583–1596

    Article  CAS  PubMed  Google Scholar 

  40. Robinson MJ, Cobb MH (1997) Mitogen-activated protein kinase pathways. Curr Opin Cell Biol 9:180–186

    Article  CAS  PubMed  Google Scholar 

  41. Kyriakis JM, Avruch J (2001) Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol Rev 81:807–869

    CAS  PubMed  Google Scholar 

  42. Kar S, Subbaram S, Carrico PM, Melendez JA (2010) Redox-control of matrix metalloproteinase-1: a critical link between free radicals, matrix remodeling and degenerative disease. Respir Physiol Neurobiol 174:299–306

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Lopes JP, Oliveira SM, Soares Fortunato J (2008) Oxidative stress and its effects on insulin resistance and pancreatic beta-cells dysfunction: relationship with type 2 diabetes mellitus complications. Acta Med Port 21:293–302

    CAS  PubMed  Google Scholar 

  44. Koli K, Myllärniemi M, Keski-Oja J, Kinnula VL (2008) Transforming growth factor-β activation in the lung: focus on fibrosis and reactive oxygen species. Antioxid Redox Signal 10:333–342

    Article  CAS  PubMed  Google Scholar 

  45. Arai K, Lee SR, Lo EH (2003) Essential role for ERK mitogen-activated protein kinase in matrix metalloproteinase-9 regulation in rat cortical astrocytes. Glia 43:254–264

    Article  PubMed  Google Scholar 

  46. Hsieh HL, Wang HH, Wu WB, Chu PJ, Yang CM (2010) Transforming growth factor-β1 induces matrix metalloproteinase-9 and cell migration in astrocytes: roles of ROS-dependent ERK- and JNK-NF-κB pathways. J Neuroinflammation 7:88

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  47. Sundararaj KP, Samuvel DJ, Li Y, Sanders JJ, Lopes-Virella MF, Huang Y (2009) Interleukin-6 released from fibroblasts is essential for up-regulation of matrix metalloproteinase-1 expression by U937 macrophages in coculture: cross-talking between fibroblasts and U937 macrophages exposed to high glucose. J Biol Chem 284:13714–13724

    Article  CAS  PubMed  Google Scholar 

  48. Lee YJ, Kim JS, Kang DG, Lee HS (2010) Buddleja officinalis suppresses high glucose-induced vascular smooth muscle cell proliferation: role of mitogen-activated protein kinases, nuclear factor-kappaB and matrix metalloproteinases. Exp Biol Med (Maywood) 235:247–255

    Article  CAS  Google Scholar 

  49. Gloire G, Legrand-Poels S, Piette J (2006) NF-kappaB activation by reactive oxygen species: fifteen years later. Biochem Pharmacol 72:1493–1505

    Article  CAS  PubMed  Google Scholar 

  50. Tai KY, Shieh YS, Lee CS, Shiah SG, Wu CW (2008) Axl promotes cell invasion by inducing MMP-9 activity through activation of NF-κB and Brg-1. Oncogene 27:4044–4055

    Article  CAS  PubMed  Google Scholar 

  51. Kam AY, Liu AM, Wong YH (2007) Formyl peptide-receptor like-1 requires lipid raft and extracellular signal-regulated protein kinase to activate inhibitor-κB kinase in human U87 astrocytoma cells. J Neurochem 103:1553–1566

    Article  CAS  PubMed  Google Scholar 

  52. Stan D, Calin M, Manduteanu I, Pirvulescu M, Gan AM, Butoi ED, Simion V, Simionescu M (2011) High glucose induces enhanced expression of resistin in human U937 monocyte-like cell line by MAPK- and NF-κB-dependent mechanisms; the modulating effect of insulin. Cell Tissue Res 343:379–387

    Article  CAS  PubMed  Google Scholar 

  53. Chen YW, Liu F, Tran S, Zhu Y, Hébert MJ, Ingelfinger JR, Zhang SL (2006) Reactive oxygen species and nuclear factor-kappa B pathway mediate high glucose-induced Pax-2 gene expression in mouse embryonic mesenchymal epithelial cells and kidney explants. Kidney Int 70:1607–1615

    Article  CAS  PubMed  Google Scholar 

  54. Lauffenburger DA, Horwitz AF (1996) Cell migration: a physically integrated molecular process. Cell 84:359–369

    Article  CAS  PubMed  Google Scholar 

  55. Mantuano E, Inoue G, Li X, Takahashi K, Gaultier A, Gonias SL, Campana WM (2008) The hemopexin domain of matrix metalloproteinase-9 activates cell signaling and promotes migration of schwann cells by binding to low-density lipoprotein receptor-related protein. J Neurosci 28:11571–11582

    Article  CAS  PubMed  Google Scholar 

  56. Shinohara M, Adachi Y, Mitsushita J, Kuwabara M, Nagasawa A, Harada S, Furuta S, Zhang Y, Seheli K, Miyazaki H, Kamata T (2010) Reactive oxygen generated by NADPH oxidase (NOX) 1 contributes to cell division by regulating matrix metalloprotease-9 production and cell migration. J Biol Chem 285:4481–4488

    Article  CAS  PubMed  Google Scholar 

  57. Yarbro JW (1992) Mechanism of action of hydroxyurea. Semin Oncol 19:1–10

    CAS  PubMed  Google Scholar 

  58. Yoon JJ, Lee YJ, Kim JS, Kang DG, Lee HS (2010) Betulinic acid inhibits high glucose-induced vascular smooth muscle cells proliferation and migration. J Cell Biochem 111:1501–1511

    Article  CAS  PubMed  Google Scholar 

  59. Kim SY, Lee JG, Cho WS, Cho KH, Sakong J, Kim JR, Chin BR, Baek SH (2010) Role of NADPH oxidase-2 in lipopolysaccharide-induced matrix metalloproteinase expression and cell migration. Immunol Cell Biol 88:197–204

    Article  CAS  PubMed  Google Scholar 

  60. Lin CC, Hsieh HL, Shih RH, Chi PL, Cheng SE, Chen JC, Yang CM (2012) NADPH oxidase 2-derived reactive oxygen species signal contributes to bradykinin-induced matrix metalloproteinase-9 expression and cell migration in brain astrocytes. Cell Commun Signal 10:35

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the Ministry of Education, Taiwan, grant numbers: EMRPD1C0261 and EMRPD1C0271; the National Science Council, Taiwan, grant numbers: NSC101-2321-B-182-013, NSC101-2320-B-182-039-MY3, NSC99-2321-B182-003, and NSC98-2320-B-255-001-MY3; and Chang Gung Medical Research Foundation, grant numbers: CMRPD180373, CMRPD1B0381, CMRPF1A0061, and CMRPF1A0062.

Conflicts of interest

None.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Chuen-Mao Yang.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(DOC 559 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hsieh, HL., Lin, CC., Hsiao, LD. et al. High Glucose Induces Reactive Oxygen Species-Dependent Matrix Metalloproteinase-9 Expression and Cell Migration in Brain Astrocytes. Mol Neurobiol 48, 601–614 (2013). https://doi.org/10.1007/s12035-013-8442-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-013-8442-6

Keywords

Navigation