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Sean Lee, D'Anne S Duncan, Franklin D Echevarria, Rebecca M Sappington; Pressure-induced PEDF signaling as a potential neuroprotectant for RGCs . Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2413.
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© ARVO (1962-2015); The Authors (2016-present)
Alterations in neuron-glia signaling are implicated in glaucoma, a neurodegenerative disease characterized by retinal ganglion cell (RGC) death. Pigment Epithelium Derived Factor (PEDF) is a secreted protein with potential neuroprotective qualities in retinal disease, including chronic ocular hypertension. Here we sought to determine whether moderate, short-term elevations in IOP alter PEDF signaling and whether pressure-induced PEDF signaling directly impacts RGC death.
In retina from naïve mice and mice with unilateral, microbead-induced glaucoma, we examined expression and cell type-specific localization of PEDF and its receptor (PEDF-R), using quantitative PCR and immunohistochemistry. Using primary cultures of purified RGCs and Müller glia, we examined cell type-specific expression and function of PEDF in response to 48 hours of elevated hydrostatic pressure. We measured pressure-induced expression and secretion of PEDF by RGCS and Müller cells, using multiplex ELISA. We also measured pressure-induced apoptosis of RGCs in the presence or absence of atglistatin, a potent and selective inhibitor of PEDF-R, using TUNEL labeling and cell density analyses.
We found that PEDF and PEDF-R are constitutively expressed in naïve retina, primarily in the ganglion cell and nerve fiber layers (p < 0.05; ANOVA with Bonferroni). Quantification of immunofluorescence revealed upregulation of both PEDF and PEDF-R in microbead retina (p < 0.05). In both normotensive and hypertensive eyes, PEDF and PEDF-R co-localized with cell type-specific markers for RGCs and Müller cells - including SMI-31, gamma synuclein, and glutamine synthetase. Elevated pressure increased PEDF expression and secretion by 6-fold in RGCs (p < 0.05) and almost 2-fold in Müller glia, as compared to ambient pressure (p > 0.05). Inhibition of PEDF signaling with atglistatin increased pressure-induced apoptosis in RGCs, as compared to elevated pressure alone (p < 0.01).
Our findings suggest that moderate, short-term elevations in IOP promote PEDF signaling via upregulation of both PEDF and PEDF-R. Based on our in vivo and in vitro studies, this PEDF signaling likely arises from both Müller cells and RGCs, and has the potential to promote survival of RGCs.
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