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D.H. Desai, G. Prasanna, D. Jung, T. Yorio; Endothelin-1-Induced Proliferation of Cultured Human Optic Nerve Head Astrocytes Involves MAPK Pathway . Invest. Ophthalmol. Vis. Sci. 2003;44(13):2248.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Optic nerve head astrocytes (ONAs) normally support and protect the axons of retinal ganglion cells exiting the eye. Along with elevated IOP-related effects, proliferation of human ONAs is also thought to contribute to the pathophysiology of glaucoma by causing ischemic damage and possible disruption of axonal transport. Levels of endothelin-1 (ET-1), a potent vasoactive peptide, are elevated in glaucomatous eyes. Recently, we have shown that ET-1 causes a time-dependent proliferation of hONAs. TNF-α, a cytokine, which is also elevated in glaucoma, promotes ET-1 release from human retinal pigmented epithelial cells. The purpose of this study was to investigate the roles of TNF-α and ET-1 in ONA proliferation and to delineate the signaling mechanisms involved. We will also examine the effect of hypoxia/ischemia, a condition prevalent in glaucoma, on the production of ET-1 by hONAs as well as on cell proliferation. Methods: A cell proliferation assay (Formazan assay) was performed on well-characterized hONAs and human brain astrocytoma U373MG cells in culture under serum free conditions. Proliferation of hONAs was measured following 96-hr treatment with TNFα and ET-1. To examine whether mitogen-activated protein kinases (MAPKs) mediated the proliferation, a MAPK inhibitor PD98059 was used. ET-1 production was measured using an ET-1 ELISA kit. Results: Both TNF-α and ET-1 were mitogenic for hONAs with TNF-α having a greater effect (250%) than ET-1 (125%). PD98059 blocked the effect of ET-1-induced proliferation both in hONA and U373MG astrocytoma cells, suggesting MAPK signaling is involved in ET-mediated astrocyte proliferation. Conclusions: The effects of TNF-α and ET-1 on promoting hONA proliferation are significant especially since these agents are elevated in glaucoma and both could promote astrogliosis in the glaucomatous optic nerve head.
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