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Progressive retinal ganglion cell (RGC) loss underlies a number of retinal neurodegenerative disorders, which may lead to permanent vision loss. However, secreted neuroprotective factors, such as PEDF, VEGF and IL-6, which are produced by Müller cells, have been shown to promote RGC survival. Assuming that the communication of RGCs with Müller cells involves a release of glioactive substances we sought to determine whether retinal neurons are able to modulate expression levels of Müller cell-derived PEDF, VEGF and IL-6. We demonstrate elevated mRNA levels of these factors in Müller cells in co-cultures with RGCs or R28 cells when compared to homotypic Müller cell cultures. Furthermore, R28 cells were more protected from apoptosis when co-cultured with Müller cells. IL-6 and VEGF were upregulated in Müller cells under hypoxia. Both cytokines, as well as PEDF, induced an altered neuronal expression of members of the Bcl-2 family, which are central molecules in the regulation of apoptosis. These results suggest that in retinal ischemia, via own secreted mediators, RGCs can resist a potential demise by stimulating Müller cells to increase production of neuroprotective factors, which counteract RGC apoptosis., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

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.