Muller glial cells (MGCs) are known to participate actively in retinal development and to contribute to homoeostasis through many intracellular mechanisms. As there are no homologous cells in other neuronal tissues, it is certain that retinal health depends on MGCs. These macroglial cells are located at the centre of the columnar subunit and have a great ability to interact with neurons, astrocytes, microglia and endothelial cells in order to modulate different events. Several investigations have focused their attention on the role of MGCs in diabetic retinopathy, a progressive pathology where several insults coexist. As expected, data suggest that MGCs display different responses according to the severity of the stimulus, and therefore trigger distinct events throughout the course of the disease. Here, we describe physiological functions of MGCs and their participation in inflammation, gliosis, synthesis and secretion of trophic and antioxidant factors in the diabetic retina. We invite the reader to consider the protective/deleterious role of MGCs in the early and late stages of the disease. In the light of the results, we open up the discussion around and ask the question: Is it possible that the modulation of a single cell type could improve or even re-establish retinal function after an injury?

A journey into the retina: Müller glia commanding survival and death.

Vascular endothelial growth factor (VEGF) is well established as the main agent responsible for vascular leakage and angiogenesis in the diabetic retina. While VEGF can have positive effects on hyperglycemia stressed retinal tissues, it also plays a role in events progressing to the oxygen- stressed, i.e. hypoxic, diabetic retina. Some VEGF makes its way to the retina from systemic sources and some is produced locally within the eye. Hyperglycemia, oxidants, inflammation, and advanced glycation end-products are all stimulants to VEGF production, both in the hypoxic and the pre-hypoxic retina. Endothelial cells, pericytes, Muller cells, microglia, astrocytes, retinal pigment epithelium and neurons have all been known to produce VEGF at some point in retinal development or in disease. Excessive VEGF production in the early diabetic retina can lead to retinal exposure or mechanisms which exacerbate further damage. While Muller cells are likely the most significant producer of VEGF in the pre-hypoxic retina, other VEGF producing cells may also play a role due to their proximity to vessels or neurons. Study of the release of VEGF by retinal cells in hyperglycemia conditions, may help identify targets for early treatment and prevent the serious consequences of diabetic retinopathy.

Autocrine and Paracrine Secretion of Vascular Endothelial Growth Factor in the Pre-Hypoxic Diabetic Retina

PPP1CA/YAP/GS/Gln/mTORC1 pathway activates retinal Müller cells during diabetic retinopathy

Purpose
Diabetic retinopathy is manifested by excessive angiogenesis and high level of vascular endothelial growth factor (VEGF) in the eye.

High Glucose and Glucose Deprivation Modulate Müller Cell Viability and VEGF Secretion.

Diabetic retinopathy (DR), the most common complication of diabetes mellitus, is associated with oxidative stress, nuclear factor-κB (NFκB) activation, and excess production of vascular endothelial growth factor (VEGF) and intracellular adhesion molecule-1 (ICAM-1). Muller glial cells, spanning the entirety of the retina, are involved in DR inflammation. Mitigation of DR pathology currently occurs via invasive, frequently ineffective therapies which can cause adverse effects. The application of far-red to near-infrared (NIR) light (630-1000nm) reduces oxidative stress and inflammation in vitro and in vivo. Thus, we hypothesize that 670nm light treatment will diminish oxidative stress preventing downstream inflammatory mechanisms associated with DR initiated by Muller cells. In this study, we used an in vitro model system of rat Muller glial cells grown under normal (5 mM) or high (25 mM) glucose conditions and treated with a 670 nm light emitting diode array (LED) (4.5 J/cm2) or no light (sham) daily. We report that a single 670 nm light treatment diminished reactive oxygen species (ROS) production and preserved mitochondrial integrity in this in vitro model of early DR. Furthermore, treatment for 3 days in culture reduced NFκB activity to levels observed in normal glucose and prevented the subsequent increase in ICAM-1. The ability of 670nm light treatment to prevent early molecular changes in this in vitro high glucose model system suggests light treatment could mitigate early deleterious effects modulating inflammatory signaling and diminishing oxidative stress.

670nm photobiomodulation modulates bioenergetics and oxidative stress, in rat Müller cells challenged with high glucose.

Muller cells have important roles in the pathogenesis of diabetic retinopathy by promoting cell proliferation and inducing the production of vascular endothelial growth factor (VEGF) under hyperglycemic conditions The objective of this study was to determine the potential mechanism of Muller cell proliferation and VEGF production due to high-glucose conditions Primary cultured rat Muller cells were incubated with medium containing variable concentrations of glucose and/or embelin, a specific inhibitor of X-linked inhibitor of apoptosis protein (XIAP), for 72 h The proliferation of Muller cells was assessed by the MTT assay The expression and/or phosphorylation of 146 proteins were assessed using protein pathway array High concentrations of glucose-induced Muller cell proliferation and altered expression and/or phosphorylation of 47 proteins that have been identified to have key roles in several important signaling pathways (XIAP, VEGF, HIF1α, NFκB, etc) and are involved in the regulation of cell survival, proliferation, or apoptosis However, Muller cell alterations induced by high-glucose conditions were counteracted by the XIAP inhibitor embelin, and 26 proteins/phosphorylations (out of 47) were restored to their normal levels Nine proteins, including NFκB p65, p-p38, tumor necrosis factor-α, urokinase-type plasminogen activator, CREB, IL-1β, HCAM, estrogen receptor-α, and p-Stat3, were involved in regulatory networks between XIAP and VEGF The current study suggests that XIAP may be a potential regulator that can mediate a series of pathological changes induced by high-glucose conditions in Muller cells Therefore, embelin could be a potential agent for the prevention and treatment of diabetic retinopathy

/pdf/elevated-cell-proliferation-and-vegf-production-by-high-24q0nsvo1f.pdf

Elevated cell proliferation and VEGF production by high-glucose conditions in Müller cells involve XIAP

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Elevated cell proliferation and VEGF production by high-glucose conditions in Müller cells involve XIAP