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Up-regulation of ROS-Dependent Matrix Metalloproteinase-9 from High-Glucose-Challenged Astrocytes Contributes to the Neuronal Apoptosis

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Abstract

An elevated level of glucose has been found in the blood of hyperglycemia and diabetes patients associated with several central nervous system (CNS) complications. These disorders may be due to the up-regulation of many neurotoxic mediators by host cells triggered by high glucose (HG). Moreover, increased plasma levels of matrix metalloproteinases (MMPs), MMP-9 especially, have been observed in patients with brain injuries and may contribute to brain diseases. However, the HG level triggers the CNS pathological responses during the hyperglycemia and diabetes remain unclear. In this study, we use a transformed astroglial cell (RBA-1) as a model to investigate the signaling mechanisms of MMP-9 induction by HG and its effects on neuronal cells. First, the data by gelatin zymographic and Western blotting analyses demonstrated that HG-induced MMP-9 expression. Next, the data obtained with selective pharmacological inhibitors and small interfering RNAs showed that HG-induced MMP-9 expression via a c-Src-dependent transactivation of platelet-derived growth factor receptor and PI3K/Akt linking to NADPH oxidase 2-derived reactive oxygen species signal and activation of MAPKs. Subsequently, the transcriptional factor AP-1 was activated and thereby turned on transcription of MMP-9 gene. Ultimately, we found that HG-induced MMP-9 expression from astrocytes resulted in neuronal apoptosis. These results will provide new insights into the mechanisms and effects of the action of HG, supporting the hypothesis that HG may cause brain disorders in the development of diabetes and hyperglycemia-induced CNS complications such as neurodegenerative diseases.

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References

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

    Article  PubMed  CAS  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  PubMed  CAS  PubMed Central  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  5. 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  PubMed  CAS  PubMed Central  Google Scholar 

  6. 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. New Engl J Med 319:548–555

    Article  PubMed  CAS  Google Scholar 

  7. Kimelberg HK (1995) Receptors on astrocytes—what possible functions? Neurochem Int 26:27–40

    Article  PubMed  CAS  Google Scholar 

  8. Levinson SW, Goldman JE (1993) Astrocyte origins. In: Murphy S (ed) Astrocytes: pharmacology and function. Academic Press, San Diego, pp 1–22

    Google Scholar 

  9. Hamby ME, Sofroniew MV (2010) Reactive astrocytes as therapeutic targets for CNS disorders. Neurotherapeutics 7:494–506

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  10. Zhao Y, Rempe DA (2010) Targeting astrocytes for stroke therapy. Neurotherapeutics 7:439–451

    Article  PubMed  CAS  Google Scholar 

  11. Verkhratsky A, Olabarria M, Noristani HN, Yeh CY, Rodriguez JJ (2010) Astrocytes in Alzheimer’s disease. Neurotherapeutics 7:399–412

    Article  PubMed  CAS  Google Scholar 

  12. Yang CM, Hsieh HL, Lin CC, Shih RH, Chi PL, Cheng SE, Hsiao LD (2013) Multiple factors from bradykinin-challenged astrocytes contribute to the neuronal apoptosis: involvement of astroglial ROS, MMP-9, and HO-1/CO system. Mol Neurobiol 47:1020–1033

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  14. 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  PubMed  CAS  Google Scholar 

  15. Gottschall PE, Yu X (1995) Cytokines regulate gelatinase A, B (matrix metalloproteinase 2 and 9) activity in cultured rat astrocytes. J Neurochem 64:1513–1520

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  PubMed Central  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  19. 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  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  21. 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  PubMed  CAS  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  PubMed  CAS  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

    PubMed  CAS  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  PubMed  CAS  Google Scholar 

  25. Tung WH, Hsieh HL, Yang CM (2010) Enterovirus 71 induces COX-2 expression via MAPKs, NF-κB, and AP-1 in SK-N-SH cells: role of PGE2 in viral replication. Cell Signal 22:234–246

    Article  PubMed  CAS  Google Scholar 

  26. 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  PubMed  CAS  Google Scholar 

  27. Reinehr R, Görg B, Becker S, Qvartskhava N, Bidmon HJ, Selbach O, Haas HL, Schliess F, Häussinger D (2007) Hypoosmotic swelling and ammonia increase oxidative stress by NADPH oxidase in cultured astrocytes and vital brain slices. Glia 55:758–771

    Article  PubMed  Google Scholar 

  28. Hsieh HL, Wu CY, Yang CM (2008) Bradykinin induces matrix metalloproteinase-9 expression and cell migration through a PKC-δ-dependent ERK/Elk-1 pathway in astrocytes. Glia 56:619–632

    Article  PubMed  Google Scholar 

  29. Hsieh HL, Wang HH, Wu CY, Tung WH, Yang CM (2010) Lipoteichoic acid induces matrix metalloproteinase-9 expression via transactivation of PDGF receptors and NF-κB activation in rat brain astrocytes. Neurotox Res 17:344–359

    Article  PubMed  CAS  Google Scholar 

  30. Wang HH, Hsieh HL, Yang CM (2010) Calmodulin kinase II-dependent transactivation of PDGF receptors mediates astrocytic MMP-9 expression and cell motility induced by lipoteichoic acid. J Neuroinflammation 7:84

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  31. Wu CY, Hsieh HL, Sun CC, Tseng CP, Yang CM (2008) IL-1β induces proMMP-9 expression via c-Src-dependent PDGFR/PI3K/Akt/p300 cascade in rat brain astrocytes. J Neurochem 105:1499–14512

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  33. Bedard K, Krause KH (2007) The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev 87:245–313

    Article  PubMed  CAS  Google Scholar 

  34. Hsieh HL, Lin CC, Shih RH, Hsiao LD, Yang CM (2012) NADPH oxidase-mediated redox signal contributes to lipoteichoic acid-induced MMP-9 upregulation in brain astrocytes. J Neuroinflammation 9:110

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  35. 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  PubMed  CAS  PubMed Central  Google Scholar 

  36. 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  PubMed  CAS  PubMed Central  Google Scholar 

  37. Ralay Ranaivo H, Hodge JN, Choi N, Wainwright MS (2012) Albumin induces upregulation of matrix metalloproteinase-9 in astrocytes via MAPK and reactive oxygen species-dependent pathways. J Neuroinflammation 9:68

    Article  PubMed  Google Scholar 

  38. Wang HH, Hsieh HL, Wu CY, Sun CC, Yang CM (2009) Oxidized low-density lipoprotein induces matrix metalloproteinase-9 expression via a p42/p44 and JNK-dependent AP-1 pathway in brain astrocytes. Glia 57:24–38

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  40. Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH (2010) Mechanisms underlying inflammation in neurodegeneration. Cell 140:918–934

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  41. 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  PubMed  CAS  Google Scholar 

  42. Wyss-Coray T (2006) Inflammation in Alzheimer disease: driving force, bystander or beneficial response? Nat Med 12:1005–1015

    PubMed  CAS  Google Scholar 

  43. Abramov AY, Jacobson J, Wientjes F, Hothersall J, Canevari L, Duchen MRL (2005) Expression and modulation of an NADPH oxidase in mammalian astrocytes. J Neurosci 25:9176–9184

    Article  PubMed  CAS  Google Scholar 

  44. Hsieh HL, Wang HH, Wu CY, Yang CM (2010) Reactive oxygen species-dependent c-Fos/activator protein 1 induction upregulates heme oxygenase-1 expression by bradykinin in brain astrocytes. Antioxid Redox Signal 13:1829–1844

    Article  PubMed  CAS  Google Scholar 

  45. 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  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  47. 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  PubMed  CAS  PubMed Central  Google Scholar 

  48. 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

    PubMed  CAS  Google Scholar 

  49. Wu WS (2006) The signaling mechanism of ROS in tumor progression. Cancer Metastasis Rev 25:695–705

    Article  PubMed  CAS  Google Scholar 

  50. Hsieh HL, Lin CC, Hsiao LD, Yang CM (2013) High glucose induces reactive oxygen species-dependent matrix metalloproteinase-9 expression and cell migration in brain astrocytes. Mol Neurobiol 48:601–614

    Article  PubMed  CAS  Google Scholar 

  51. Kennedy KA, Sandiford SD, Skerjanc IS, Li SS (2012) Reactive oxygen species and the neuronal fate. Cell Mol Life Sci 69:215–221

    Article  PubMed  CAS  Google Scholar 

  52. Sen CK, Packer L (1996) Antioxidant and redox regulation of gene transcription. FASEB J 10:709–720

    PubMed  CAS  Google Scholar 

  53. Woo CH, Lim JH, Kim JH (2004) Lipopolysaccharide induces matrix metalloproteinase-9 expression via a mitochondrial reactive oxygen species-p38 kinase-activator protein-1 pathway in Raw 264.7 cells. J Immunol 173:6973–6980

    Article  PubMed  CAS  Google Scholar 

  54. Byun HJ, Hong IK, Kim E, Jin YJ, Jeoung DI, Hahn JH, Kim YM, Park SH, Lee H (2006) A splice variant of CD99 increases motility and MMP-9 expression of human breast cancer cells through the AKT-, ERK-, and JNK-dependent AP-1 activation signaling pathways. J Biol Chem 281:34833–34847

    Article  PubMed  CAS  Google Scholar 

  55. 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  PubMed  CAS  Google Scholar 

  56. Li H, Mittal A, Paul PK, Kumar M, Srivastava DS, Tyagi SC, Kumar A (2009) Tumor necrosis factor-related weak inducer of apoptosis augments matrix metalloproteinase 9 (MMP-9) production in skeletal muscle through the activation of nuclear factor-κB-inducing kinase and p38 mitogen-activated protein kinase: a potential role of MMP-9 in myopathy. J Biol Chem 284:4439–4450

    Article  PubMed  CAS  PubMed Central  Google Scholar 

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Acknowledgments

This work was supported by the Ministry of Education, Taiwan, grant number: EMRPD1D0231 and EMRPD1D0241; National Science Council, Taiwan, grant number: NSC102-2321-B-182-011, NSC101-2320-B-182-039-MY3, and NSC102-2320-B-255-005-MY3; Chang Gung Medical Research Foundation, grant number: CMRPD1B0382, CMRPD1C0101, CMRPD1C0561, CMRPF1A0063, CMRPG5C0061, CMRPG391033, and CMRPG3B1092.

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Authors and Affiliations

  1. Department of Nursing, Division of Basic Medical Sciences, Chang Gung University of Science and Technology, Kwei-San, Tao-Yuan, Taiwan

    Hsi-Lung Hsieh

  2. Department of Physiology and Pharmacology and Health Ageing Research Center, College of Medicine, Chang Gung University, 259 Wen-Hwa 1st Road, Kwei-San, Tao-Yuan, Taiwan

    Pei-Ling Chi, Chien-Chung Yang & Chuen-Mao Yang

  3. Department of Anesthetics, Chang Gung Memorial Hospital at Lin-Kou and College of Medicine, Chang Gung University, Kwei-San, Tao-Yuan, Taiwan

    Chih-Chung Lin

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  1. Hsi-Lung Hsieh
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Correspondence to Chuen-Mao Yang.

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Hsieh, HL., Chi, PL., Lin, CC. et al. Up-regulation of ROS-Dependent Matrix Metalloproteinase-9 from High-Glucose-Challenged Astrocytes Contributes to the Neuronal Apoptosis. Mol Neurobiol 50, 520–533 (2014). https://doi.org/10.1007/s12035-013-8628-y

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