Pigment Epithelium-Derived Factor (PEDF) Receptors Are Involved in Survival of Retinal Neurons.

Susanne Bürger,Mike Beck,Wolfram Eichler,Maik Pankonin,Jie Meng,Jan Darius Unterlauft,Peter Wiedemann,Annette Zwanzig

doi:10.3390/ijms22010369

Abstract

The demise of retinal ganglion cells (RGCs) is characteristic of diseases of the retina such as glaucoma and diabetic or ischemic retinopathies. Pigment epithelium-derived factor (PEDF) is a multifunctional secreted protein that mediates neuroprotection and inhibition of angiogenesis in the retina. We have studied expression and regulation of two of several receptors for PEDF, patatin-like phospholipase 2 gene product/PEDF-R and laminin receptor (LR), in serum-starved RGC under normoxia and hypoxia and investigated their involvement in the survival of retinal neuronal cells. We show that PEDF-R and LR are co-expressed in RGC and R28 retinal precursor cells. Expression of both receptors was enhanced in the presence of complex secretions from retinal glial (Müller) cells and upregulated by VEGF and under hypoxic conditions. PEDF-R- and LR-knocked-down cells demonstrated a markedly attenuated expression of anti-apoptotic Bcl-2 family members (Bcl-2, Bcl-xL) and neuroprotective mediators (PEDF, VEGF, BDNF) suggesting that both PEDF-R and LR mediate pro-survival effects of PEDF on RGC. While this study does not provide evidence for a differential survival-promoting influence of either PEDF-R or LR, it nevertheless highlights the importance of both PEDF receptors for the viability of retinal neurons.

Highlights

Degeneration of retinal neurons is involved in sight-threatening eye diseases, such as glaucoma and ischemic retinopathies, which lead to blindness if not adequately treated
To address the role of pigment epithelium-derived factor (PEDF) receptors in retinal ganglion cells (RGCs), we analyzed expression of PEDF-R and laminin receptor (LR) in retinal neuronal cells in experiments mimicking conditions that contribute to the pathogenesis of retinal degenerative diseases
Our present study suggests that PEDF-R and LR are co-expressed in retinal neuronal cells including RGC and that both molecules may have an important function for maintaining neuronal survival, in particular, under hypoxia

Summary

Introduction

Degeneration of retinal neurons is involved in sight-threatening eye diseases, such as glaucoma and ischemic retinopathies, which lead to blindness if not adequately treated. The worldwide prevalence of glaucoma, where progressive degeneration and programmed cell death (i.e., apoptosis) of RGC play a major pathogenic role, is estimated to exceed 110 million by the year 2040 [1]. There are still important questions regarding mechanisms of action related to neuroprotective factors that need to be answered. Müller glial cells are an important source for cytoprotective factors that promote viability and survival of neurons, in particular, in response to various pathological external influences. Conditional Müller cell ablation in mice led to apoptosis of photoreceptors, highlighting the consequences of Müller cell dysfunction and indicating that neuron–glia interactions and glial trophic support have an important role to play for maintaining neuronal viability [2]. Among trophic Müller cell-derived mediators are, for example, pigment epithelium-derived factor (PEDF), brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor-A (designated hereafter as VEGF), interleukin (IL)-6, ciliary neurotrophic factor and glial-derived neurotrophic factor [3,4,5,6,7,8,9,10,11]

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