Nerve growth factor inhibits osmotic swelling of rat retinal glial (Müller) and bipolar cells by inducing glial cytokine release

Abstract

Osmotic swelling of neurons and glial cells contributes to the development of retinal edema and neurodegeneration. We show that nerve growth factor (NGF) inhibits the swelling of glial (M€ uller) and bipolar cells in rat retinal slices induced by barium-containing hypoosmotic solution. NGF also reduced M€ uller and bipolar cell swelling in the post-ischemic retina. On the other hand, NGF prevented the swelling of freshly isolated M€ uller cells, but not of isolated bipolar cells, suggesting that NGF induces a release of factors from M€ uller cells that inhibit bipolar cell swelling in retinal slices. The inhibitory effect of NGF on M€ uller cell swelling was mediated by activation of TrkA (the receptor tyrosine kinase A), but not p75 NTR , and was prevented by blockers of metabotropic glutamate, P2Y 1 , adenosine A 1 , and fibroblast growth factor receptors. Basic fibroblast growth factor fully inhibited the swelling of freshly isolated M€ uller cells, but only partially the swelling of isolated bipolar cells. In addition, glial cell line-derived neurotrophic factor and transforming growth factor-b1, but not epidermal growth factor and platelet-derived growth factor, reduced the swelling of bipolar cells. Both M€ uller and bipolar cells displayed TrkA immunoreactivity, while M€ uller cells were also immunostained for p75 NTR and NGF. The data suggest that the neuroprotective effect of NGF in the retina is in part mediated by prevention of the cytotoxic glial and bipolar cell swelling.

Endothelins Inhibit Osmotic Swelling of Rat Retinal Glial and Bipolar Cells by Activation of Growth Factor Signaling

“…We found that, in contrast to ET-1, ET-2 osmotic swelling of bipolar cell somata in retinal slices is an indirect effect, likely mediated by ET-1-induced release of swelling-inhibitory factors from Müller cells. It has been shown that ETs induce a release of growth factors like bFGF from Müller cells [15,31] and that bFGF and TGF-β1 inhibit in part the osmotic swelling of isolated bipolar cells [13]. We found that the inhibitory effect of ET-1 on the osmotic swelling of bipolar cells in retinal slices is abrogated in the presence of inhibitors of the FGF receptor tyrosine kinase and of TGF-β1 superfamily activin receptor-like kinase receptors.…”

“…In addition, the outer processes of both cell types display different morphologies, i.e., bipolar cells have a short and thick dendritic tree which contacts the synapses in the outer plexiform layer whereas Müller cells have one relatively thin outer stem process which draws to the outer nuclear layer. In previous experiments, the cellular identity was additionally confirmed by immunohistochemical staining of retinal slices for the Müller cell marker glutamine synthetase and the bipolar cell marker protein kinase Cα [13,42].…”

“…Candidate factors that may be released from Müller cells upon stimulation with ETs are growth factors such as bFGF [15,31]. bFGF and transforming growth factor (TGF)-β1 were shown to inhibit in part the osmotic swelling of isolated bipolar cells [13]. As shown in Fig.…”

“…Müller and bipolar cell somata in retinal slices were identified as recently described [13,42]. Müller cell somata are localized to the central part of the inner nuclear layer, while bipolar cell bodies are localized to the outer part of this layer.…”

“…The Müller cell volume homeostasis depends on passive potassium currents through inwardly rectifying potassium (Kir) channels [28] and on activation of a glutamatergicpurinergic signal transduction cascade resulting in the opening of potassium and chloride channels in the plasma membrane [41]. Various neuroprotective factors including vascular endothelial growth factor, erythropoietin, nerve growth factor, and brain-derived neurotrophic factor activate this signaling cascade [1,13,22,43]. Because cell volume homeostasis is crucial to prevent activity-dependent decreases of the extracellular space volume [40], which otherwise will cause neuronal hyperexcitation [12], inhibition of cytotoxic cell swelling is a neuroprotective mechanism.…”