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Chun Yang, Josiane Lafleur, Bupe R. Mwaikambo, Tang Zhu, Carmen Gagnon, Sylvain Chemtob, Adriana Di Polo, Pierre Hardy; The Role of Lysophosphatidic Acid Receptor (LPA1) in the Oxygen-Induced Retinal Ganglion Cell Degeneration. Invest. Ophthalmol. Vis. Sci. 2009;50(3):1290-1298. doi: 10.1167/iovs.08-1920.
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purpose. Although previous studies have demonstrated that hypoxia induces retinal ganglion cell (RGC) apoptosis and that transient retinal ischemia upregulates the expression of lysophosphatidic acid (LPA) receptors, it remains to be determined whether LPA1 receptor mediates RGC degeneration during retinopathy of prematurity (ROP). By using an immortalized RGC line (RGC-5), primary neonatal RGC cultures, and oxygen-induced retinopathy (OIR) to model ROP, the authors explored whether LPA1 receptor induces RGC degeneration and the potential mechanisms thereof.
methods. OIR was induced by exposing rat pups to alternating cycles of hyperoxia/hypoxia from postnatal day (P) 0 to P14. RGC viability was evaluated by Fluorogold labeling. Effects of hyperoxia or hypoxia on LPA1 expression were determined in the RGC-5 line by Western blot. Roles of hypoxia, LPA1 receptor (with agonist, stearoyl-LPA; antagonist, THG1603; LPA1 knock-down, shRNA-LPA1), and Rho kinase (with inhibitor Y-27632) in mediating RGC survival and neurite outgrowth were assessed by MTT assay and phase-contrast microscopy, respectively. Expression of GFP-LPA1 in RGC-5 under hypoxia was examined by confocal microscopy.
results. OIR caused pronounced RGC loss in the retina. LPA1 receptor was expressed by RGCs in retinal tissue, whereas oxygen stress induced its expression in RGC-5. Exposure to stearoyl-LPA or hypoxia substantially reduced the viability of RGCs; this was abrogated by THG1603 and shRNA-LPA1. THG1603 and Y-27632 treatment also attenuated the adverse effects of hypoxia on RGC-5 neurite outgrowth, and their intravitreal administration prevented OIR-induced RGC loss. Interestingly, overexpression of LPA1 increased RGC-5 susceptibility to hypoxia-induced cell loss.
conclusions. Current data strongly support a critical role for LPA1 receptor in mediating RGC degeneration during OIR.
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