Upregulation of the endothelin A (ETA) receptor and its association with neurodegeneration in a rodent model of glaucoma

Abstract

BackgroundPrimary open angle glaucoma is a heterogeneous group of optic neuropathies that results in optic nerve degeneration and a loss of retinal ganglion cells (RGCs) ultimately causing blindness if allowed to progress. Elevation of intraocular pressure (IOP) is the most attributable risk factor for developing glaucoma and lowering of IOP is currently the only available therapy. However, despite lowering IOP, neurodegenerative effects persist in some patients. Hence, it would be beneficial to develop approaches to promote neuroprotection of RGCs in addition to IOP lowering therapies. The endothelin system is a key target for intervention against glaucomatous neurodegeneration. The endothelin family of peptides and receptors, particularly endothelin-1 (ET-1) and endothelin B (ETB) receptor, has been shown to have neurodegenerative roles in glaucoma. The purpose of this study was to examine changes in endothelin A (ETA) receptor protein expression in the retinas of adult male Brown Norway rats following IOP elevation by the Morrison’s model of ocular hypertension and the impact of ETA receptor overexpression on RGC viability in vitro.ResultsIOP elevation was carried out in one eye of Brown Norway rats by injection of hypertonic saline through episcleral veins. After 2 weeks of IOP elevation, immunohistochemical analysis of retinal sections from rat eyes showed an increasing trend in immunostaining for ETA receptors in multiple retinal layers including the inner plexiform layer, ganglion cell layer and outer plexiform layer. Following 4 weeks of IOP elevation, a significant increase in immunostaining for ETA receptor expression was found in the retina, primarily in the inner plexiform layer and ganglion cells. A modest increase in staining for ETA receptors was also found in the outer plexiform layer in the retina of rats with IOP elevation. Cell culture studies showed that overexpression of ETA receptors in 661W cells as well as primary RGCs decreases cell viability, compared to empty vector transfected cells. Adeno-associated virus mediated overexpression of the ETA receptor produced an increase in the ETB receptor in primary RGCs.ConclusionsElevated IOP results in an appreciable change in ETA receptor expression in the retina. Overexpression of the ETA receptor results in an overall decrease in cell viability, accompanied by an increase in ETB receptor levels, suggesting the involvement of both ETA and ETB receptors in mediating cell death. These findings raise possibilities for the development of ETA/ETB dual receptor antagonists as neuroprotective treatments for glaucomatous neuropathy.Electronic supplementary materialThe online version of this article (doi:10.1186/s12868-017-0346-3) contains supplementary material, which is available to authorized users.

Prognostic importance of endothelin-1 and endothelin receptor: a plasma levels in the early perimetric stage of primary open-angle glaucoma

“…The results showed that each year added to the age increases the possibility for early glaucoma changes to appear 1.243 times. It is well established that glaucoma is an age-related disease [18], which was supported by our results. Every 1 pg/mL increase in the ET-1 plasma concentration increased the possibility for early glaucoma changes to appear by 2.124 times.…”

“…The progression of the disease is related to some degree of restoration of ETR-A, whereas ET-1 is permanently high. These observations are related to some theories about the glaucoma pathogenesis [18], but require further investigation.…”

“…It may be considered that the ET-1 and ETR-A levels are important in the early glaucoma stages. Therefore, they show potential for development of an ETR-A antagonist that may be applied in early glaucoma and prevent the progression of the disease, as suggested by other researchers as well [18].…”

“…It is the most potent constrictor for small and medium size blood vessels [17]. The presence of ET and the expression of their receptors have been established in the following ocular tissues: trabecular meshwork, ciliary body, lamina cribrosa and retina [18]. It is considered that ET-1 takes part in regulating the ocular blood flow, the outflow of aqueous humour from the anterior eye segment and consequently the intraocular pressure (IOP) [7].…”

Stellenwert von Endothelin-1 beim Glaukom – ein kurzer Überblick

“…Glaukompatienten, die eine Schadensprogression aufweisen, haben im Vergleich zu den Glaukompatienten mit stagnierendem Schaden einen erhöhten Plasmaendothelinspiegel [39]. Im Weiteren ist die Rolle des Endothelins beim Glaukom nicht nur auf die Regulation der Perfusion beschränkt; kürzlich publizierte Studien zeigen, dass eine Überexpression der ET-Rezeptoren nach der Stimulation durch den erhöhten Augendruck sowohl im anterioren als auch im posterioren Augensegment bei Ratten stattfindet [40]. Somit kann Endothelin sowohl bei der Regulation des Augendruckes als auch bei der Steuerung der Neurodegeneration beteiligt sein.…”