Endothelin B Receptors Contribute to Retinal Ganglion Cell Loss in a Rat Model of Glaucoma

Abstract

Glaucoma is an optic neuropathy, commonly associated with elevated intraocular pressure (IOP) characterized by optic nerve degeneration, cupping of the optic disc, and loss of retinal ganglion cells which could lead to loss of vision. Endothelin-1 (ET-1) is a 21-amino acid vasoactive peptide that plays a key role in the pathogenesis of glaucoma; however, the receptors mediating these effects have not been defined. In the current study, endothelin B (ETB) receptor expression was assessed in vivo, in the Morrison's ocular hypertension model of glaucoma in rats. Elevation of IOP in Brown Norway rats produced increased expression of ETB receptors in the retina, mainly in retinal ganglion cells (RGCs), nerve fiber layer (NFL), and also in the inner plexiform layer (IPL) and inner nuclear layer (INL). To determine the role of ETB receptors in neurodegeneration, Wistar-Kyoto wild type (WT) and ETB receptor-deficient (KO) rats were subjected to retrograde labeling with Fluoro-Gold (FG), following which IOP was elevated in one eye while the contralateral eye served as control. IOP elevation for 4 weeks in WT rats caused an appreciable loss of RGCs, which was significantly attenuated in KO rats. In addition, degenerative changes in the optic nerve were greatly reduced in KO rats compared to those in WT rats. Taken together, elevated intraocular pressure mediated increase in ETB receptor expression and its activation may contribute to a decrease in RGC survival as seen in glaucoma. These findings raise the possibility of using endothelin receptor antagonists as neuroprotective agents for the treatment of glaucoma.

Calcium Dobesilate Prevents Neurodegeneration and Vascular Leakage in Experimental Diabetes

“…41,42 In addition, it is worth mentioning that through ETB-R, ET-1 contributes to retinal ganglion cell loss in rat models of glaucoma and optic nerve injury. 23,43 Moreover, progressive retinal neurodegeneration Figure 6. A) Retinal glutamate levels from db/db mice treated with vehicle (black bar; n = 6), db/db mice treated with CaD (grey bar; n = 6), and non-diabetic (db/+) mice (white bar; n = 6).…”

“…This is an important issue because ET-1 exerts its functions via binding to two classes of G-protein coupled receptors: endothelin A (ETA) and endothelin B (ETB) receptors, both expressed in the retina. 21,22 Notably, ETB receptor expression has been reported in retinal neurons 23 and could be a key mediator of the neurodegenerative effects of ET-1 in the diabetic retina. Therefore, the inhibition of ET-1 could lead not only to an improvement in microvascular hemodynamics in the retina, but also an amelioration of the retinal neurodegeneration associated with diabetes.…”

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

“…In diabetic retinopathy, increased level of retinal ET-1 and activation of ET A receptors are associated with vascular pathology, decreased retinal blood flow, and neurodegeneration [7,24]. Activation of ET B receptors induces retinal ganglion cell death in experimental glaucoma and after optic nerve injury [26,39]. Overexpression of endothelial ET-1 in mice contributes to glutamate toxicity and water accumulation in the inner ischemic retina resulting in retinal edema [6].…”

“…Because activation of ET B contributes to the retinal ganglion cell loss in glaucoma and after optic nerve injury [26,39], it has been suggested that ET receptor antagonists may be useful as neuroprotective agents for the treatment of glaucoma [36]. …”

Non-Traditional Systemic Treatments for Diabetic Retinopathy: An Evidence-Based Review

“…This could be important for explaining not only the improvement in microvascular hemodynamic, but also the amelioration of retinal neurodegeneration associated with diabetes. In this regard, it should be noted that endothelin has recently been shown to be involved in diabetes-induced neuroretinal degeneration and, therefore, its inhibition seems a promising therapeutic target in DR [82][83][84].…”