Up-regulation of ROS-Dependent Matrix Metalloproteinase-9 from High-Glucose-Challenged Astrocytes Contributes to the Neuronal Apoptosis
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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.
KeywordsHigh glucose Astrocytes Reactive oxygen species Matrix metalloproteinase-9 Neuronal apoptosis
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.
Conflict of Interest
- 8.Levinson SW, Goldman JE (1993) Astrocyte origins. In: Murphy S (ed) Astrocytes: pharmacology and function. Academic Press, San Diego, pp 1–22Google 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 10:35PubMedCrossRefPubMedCentralGoogle 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 26:1346–1355PubMedCrossRefGoogle 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 281:34833–34847PubMedCrossRefGoogle 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 284:4439–4450PubMedCrossRefPubMedCentralGoogle Scholar