Endothelin B Receptor in Human Glaucoma and Experimentally Induced Optic Nerve Damage (original) (raw)
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Endothelin, astrocytes and glaucoma
Experimental Eye Research, 2011
It has become increasingly clear that astrocytes may play an important role in the genesis of glaucoma. Astrogliosis occurs in response to ocular stress or the presence of noxious stimuli. Agents that appear to stimulate reactive gliosis are becoming increasingly clear. One class of agents that is emerging is the endothelins (ETs; specifically, ET-1). In this review we examine the interactions of ET-1 with astrocytes and provide examples where ET-1 appears to contribute to activation of astrocytes and play a role in the neurodegenerative effects that accompany such reactivation resulting in astrogliosis. These actions are presented in the context of glaucoma although information is also presented with respect to ET-1's role in the central nervous system and brain. While much has been learned with respect to ET-1/astrocyte interactions, there are still a number of questions concerning the potential therapeutic implications of these findings. Hopefully this review will stimulate others to examine this potential.
Endothelin B Receptors Contribute to Retinal Ganglion Cell Loss in a Rat Model of Glaucoma
PLoS ONE, 2012
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 (ET B ) 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 ET B 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 ET B receptors in neurodegeneration, Wistar-Kyoto wild type (WT) and ET B 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 ET B 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.
Human Optic Nerve Head Astrocytes as a Target for Endothelin1
2002
PURPOSE. To determine whether human optic nerve head as- trocytes (hONAs) are target cells for the actions of endothelin (ET)-1, a potent vasoactive peptide, by causing astrocyte pro- liferation, as occurs in glaucomatous optic nerve heads. ET-1 levels are elevated in glaucomatous eyes, and administration of ET-1 to the retina causes glial activation and optic nerve dam- age in animal
Brain Research, 2001
We have investigated the localisation of endothelin-1 (ET-1) mRNA and ET-1-like immunoreactivity in retina and anterior portion of optic nerve from human and porcine eyes. In situ hybridisation method revealed expression of ET-1 mRNA mainly in the innermost layers of the retinas, in the retinal pigment epithelium cells as well as in the astrocytes of the optic nerve. Immunohistochemical studies showed that ET-1-like immunoreactivity appeared in the same regions where ET-1 mRNA was expressed as well as in the inner nuclear layer and in the inner segments of photoreceptors. In the nerve fibre and ganglion cell layers, astrocytes expressed both glial fibrillary acidic protein and ET-1 proteins suggesting that these cells may secrete ET-1. Expression of ETA and ETB receptors in human retina were demonstrated by reverse transcription-polymerase chain reaction. Our results demonstrated expression of ET-1 in glial, neural and vascular components of retina and optic nerve from human and porcine eyes.
Effect of elevated intraocular pressure on endothelin-1 in a rat model of glaucoma
Pharmacological Research, 2005
The role of endothelin-1 (ET-1) a potent vasoactive peptide, in glaucoma pathogenesis is receiving increasing attention, particularly in astroglial activation in optic nerve damage. Our laboratory has also shown that ET-1 treatment causes proliferation of cultured human optic nerve head astrocytes to possibly initiate astrogliosis. ET-1 is distributed in retina, optic nerve, and ciliary epithelium, however the effects of elevated intraocular pressure (IOP) (as seen in glaucoma) on ET-1 and ET B receptors are not clearly understood. In the present study, the levels of immunoreactive ET-1 (ir-ET-1) in aqueous humour (AH) and optic nerve head (ONH) were determined in the Morrison elevated IOP model of glaucoma. Additionally in the ONH of these rats, immunohistochemical analyses of ET B receptors and glial fibrillary acidic protein (GFAP; a marker for astroglial cells and for astrogliosis) were performed. There was 2-to 2.5-fold increase in AH ir-ET-1 levels for rats subjected to elevated IOP, compared to their respective controls. In the Morrison rat model of glaucoma, elevated IOP increased optic nerve ir-ET-1 with concomitant increases in ir-ET B and ir-GFAP labelling (possibly indicative of astrogliosis and hypertrophy). As seen in brain astrocytes subjected to neurotrauma, the present findings are suggestive of ET-1's role in astroglial activation, particularly in response to elevated IOP in glaucoma.
Brain research, 2001
We have investigated the localisation of endothelin-1 (ET-1) mRNA and ET-1-like immunoreactivity in retina and anterior portion of optic nerve from human and porcine eyes. In situ hybridisation method revealed expression of ET-1 mRNA mainly in the innermost layers of the retinas, in the retinal pigment epithelium cells as well as in the astrocytes of the optic nerve. Immunohistochemical studies showed that ET-1-like immunoreactivity appeared in the same regions where ET-1 mRNA was expressed as well as in the inner nuclear layer and in the inner segments of photoreceptors. In the nerve fibre and ganglion cell layers, astrocytes expressed both glial fibrillary acidic protein and ET-1 proteins suggesting that these cells may secrete ET-1. Expression of ETA and ETB receptors in human retina were demonstrated by reverse transcription-polymerase chain reaction. Our results demonstrated expression of ET-1 in glial, neural and vascular components of retina and optic nerve from human and porcine eyes.
Effects of acute delivery of endothelin-1 on retinal ganglion cell loss in the rat
Experimental Eye Research, 2006
The vasoconstrictive peptide, Endothelin-1 (ET-1) has been found at elevated levels in glaucomatous eyes. In this study, a single 5 ml intraocular injection of ET-1 was injected into the rat eye in order to characterize an in vivo retinal ganglion cell (RGC)-specific cell death model. The most effective concentration of ET-1 at inducing RGC loss at 2 weeks post-injection was determined using 5, 50 and 500 mM concentrations of ET-1. The density of surviving RGCs was determined by counting Fluorogold labelled RGCs. A significant loss (25%) of RGCs was observed using only the 500 mM concentration when compared to PBS-injected controls. GFAP immunohistochemistry revealed an increase in GFAP expression in Müller cell end-feet, as well as a total increase in GFAP expression (80%), following ET-1 treatment. These changes in GFAP expression are indicative of glial hyperactivity in response to stress. The specificity of ET-1 mediated cell death for RGCs was determined by measuring the changes in retinal thickness and TUNEL labeling. Retinal thickness was quantified using confocal and light microscopy. In confocal measurements, Yo Pro-1 was used to stain nuclear layers and the thickness of retinal layers determined from reconstructions. No significant loss in thickness was observed in any retinal layers. The same observations were seen in semi-thin sections when viewed by conventional transmitted light microscopy. The lack of significant thickness changes in the outer nuclear, outer plexiform or inner nuclear layer suggests that there was no significant cell loss in the retina other than in the RGC layer. Exclusive co-localization of TUNEL-labelled nuclei with Fluorogold-labelled cytoplasm provided additional evidence for RGC-specific death that most likely occurs via an apoptotic mechanism. A cell death time course was performed to determine RGC loss over time. RGC losses of 25, 25, 36 and 44% were observed at 1, 2, 3 and 4 weeks post-ET-1 injection, compared to PBS-injected controls. The total number of remaining RGC axons was determined by multiplying the number of optic nerve (ON) axons per unit area, by the cross-sectional area. There was a 31% loss in total ON axons in ET-1 treated eyes at 3 weeks post injection. Functional integrity of the visual system was determined by observing changes in the pupillary light reflex. ET-1 treatment resulted in a slowing of the pupil velocity by 31% and an average increase in the duration of contraction of 1.85 sec (32% increase). These experiments provide evidence that acute ET-1 injections can produce RGC-specific cell death and many cellular changes that are similar to glaucoma. This potential glaucoma model leaves the optic nerve intact and may be used in subsequent experiments, which are involved in increasing RGC survival and functional recovery.
Endothelin-1 and endothelin receptors in light-induced retinal degeneration
Experimental Eye Research, 2005
We have studied the distribution of endothelinergic molecules: prepro-endothelin-1 (PPET-1), endothelin-1 (ET-1), and receptors A and B (ET-A) and (ET-B) in the retina of mice. The localization of these molecules in normal mice was compared to their localization in retinas from animals submitted to continuous illumination during 1, 6, 9 or 18 days. We also evaluated the distribution of smooth muscle actin (SMA) and glial markers, glial fibrillary acidic protein (GFAP) and glutamine synthase (GS). PPET-1 immunoreactivity mainly appeared in retinal pigment epithelium (RPE) and cells of the ganglion cell layer (GCL), whereas ET-1 immunoreactivity was present in the RPE, outer plexiform layer (OPL) and astrocytes. Astrocytes exhibited the strongest immunostaining in the retina. ET-A immunoreactivity was observed in endothelium, RPE, OPL and cells of the GCL. By contrast, ET-B immunoreactivity could be detected in endothelial cells, horizontal cells and astrocytes. Astrocytes of the optic nerve also exhibited ET-1, ET-A, and ET-B immunoreactivities. After light-induced degeneration, there was an increase of RPE immunostaining. Degeneration of photoreceptors was accompanied by disappearance of immunoreactivity in the OPL. However, ET-A immunoreactivity appeared in the amacrine sublayer of the INL. There was an enormous increase in astrocytes and its cell processes. The increase of astrocytic immunoreactivities for ET-1 and ET-B was confirmed by quantitative image analysis. Growth of astrocytic cell processes was most marked around retinal blood vessels. Our findings indicate that there are at least three endothelinergic pathways in the normal retina: (1) between the RPE and choriocapillaris, (2) at the OPL, and (3) between blood vessels, astrocytes and cells of the GCL. After light-induced degeneration of photoreceptors, endothelinergic molecules were overexpressed at the RPE and astrocytes, but mostly disappeared from the OPL.
An immunohistochemical study of endothelin-1 in the human eye
Current Eye Research, 1998
Purpose. Endothelin-1 (ET-1) is a potent vasoconstrictive and neural peptide that has been demonstrated to be present and functionally active and important in the eye. This study was undertaken to examine for the first time the cellular distribution of ET-1 in the whole human eye.