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B. Liu, A.H. Neufeld; Marked Changes in Gene Expression of Optic Nerve Astrocytes Upon Activation of Epidermal Growth Factor Receptors . Invest. Ophthalmol. Vis. Sci. 2005;46(13):1280.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose:The epidermal growth factor receptor (EGFR) is activated in reactive astrocytes in the human glaucomatous optic nerve head. EGFR is a key signaling pathway in the synthesis of inducible nitric oxide synthase and leads to cell proliferation and morphological changes in astrocytes. To further characterize the cellular responses of reactive astrocytes to the activation of EGFR in glaucomatous optic neuropathy, we have determined the gene expression profiles of optic nerve astrocytes exposed to EGF by using Affymetrix GeneChip microarrays. Methods: Rat optic nerve astrocytes were treated with or without EGF for 4 hrs. mRNA was isolated and processed to hybridize with rat genomic chips, Rat 230_2_0. Microarray data were analyzed using an Affymetrix format and normalized using Spotfire software. We selected genes whose average expression level increased or decreased more than 5 fold. Expression of selected genes was confirmed by RT–PCR. Results: There were 219 genes significantly up–regulated within 4 hrs of treatment with EGF, of which the expressions of 83 genes changed from absent in controls to present in EGF treated astrocytes. The expression of 76 genes decreased, of which 36 genes changed from present in controls to absent in EGF treated astrocytes. Among the genes highly responsive to the activation of EGFR in astrocytes are those involved in extracellular matrix turnover, such as plasminogen activator inhibitor 2A, plasminogen activator, plasminogen activator receptor, hyaluronan synthase 2, and matrix metalloproteinase 3, genes involved in cell growth, such as amphiregulin, nerve growth factor beta, fibroblast growth factor 2, and leukemia inhibitory factor, genes involved in inflammation, such as phospholipase A2, interleukin 11, bradykinin receptor b2, arginase 1, and arginosuccinate synthetase and genes related to neuronal injuries, such as endothelin converting enzyme 1 and sterol–C4–methyl oxidase. Conclusions: The marked upregulation of amphiregulin, which is an EGFR ligand, indicates that these astrocytes are being continuously activated in an autocrine manner. The EGFR–dependent expression of this wide variety of genes suggests a phenotypic change in reactive astrocytes that may contribute to the pathogenesis of glaucomatous optic neuropathy.
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