Implication of Müller glia in glaucoma

Abstract

AbstractGlaucoma is a neurodegenerative disease and the leading cause of irreversible blindness in the world, whose main risk factor is increased intraocular pressure. When visual problems are first detected in patients with glaucoma, already half of the retinal ganglion cells (RGCs), the neurons that send visual information from the eye to the brain, have died principally in the peripheral retina. The timeframe of cell death is prolonged, lasting even decades after an initial diagnosis. Müller glia (MG) are the main macroglial cell in the retina, play prominent roles regulating normal and pathological physiology and react to neuronal injury in glaucoma. The change to a reactive phenotype of MG initiates signalling cascades that may serve a neuroprotective role, but may also proceed to promote damaging effects on RGCs. However, the underlying mechanisms and signalling pathways that specifically promote protective versus destructive roles of reactive glial cells are mostly unclear.Our main hypothesis is that MGs exert an important role in the death of RGCs in glaucoma with the MGs in the periphery being the most sensitive to intraocular pressure, promoting the death of RGCs. Preventing MG response to elevated pressure, MG can neuroprotect RGCs in early stages of glaucoma.We have proved in vitro, that in control condition MG secret neuroprotective factors, and under elevated pressure MG are the responsible for the RGCs death, being less sensitive to the elevated hydrostatic pressure (EHP) the MG present in the central retina. Moreover, stretch‐activated nonselective TRPV4 cation channels present in MG are differently activated by the pressure depending of their location within the retina. Proteomic analysis from the conditioned media (CM) of MG revealed different protein expression levels being more pronounced in the CM from MG from peripheral retina in EHP. Proteins identified correspond mainly to functions such as: apoptosis, oxidative stress, inflammation and angiogenesis.We conclude that the different sensibility of the RGCs to pressure in glaucoma could be related with the different activation of the neighbours MG.