Endothelin Receptor-Binding Subtypes in the Human Retina and Choroid

MacCumber, Mathew W.; D’Anna, Salvatore A.

doi:10.1001/archopht.1994.01090210119024

Cited by 69 publications

(50 citation statements)

References 28 publications

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“…Using S6 c and BQ123, we also observed that the ETB receptor is more abundant than the ETA in all layers of the retina. In agreement, it has been previously reported that in human and rat eyes the ETA receptors were associated with the retinal and choroidal blood vessels, whereas the ETB receptors were located mainly on the neurones or glial cells, or both, of the retina [15,16]. The sections from untreated STZ-diabetic rats at 90 days after STZ injection showed a pattern of 125 I-ET-1 receptor distribution similar to that of age-matched control rats.…”

Section: Discussionsupporting

confidence: 90%

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Changes in the density and localisation of endothelin receptors in the early stages of rat diabetic retinopathy and the effect of insulin treatment

et al. 2000

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The endothelins (ETs) are a family of 2500 M r peptides with three distinct isoforms, endothelin-1, ±2 and ±3 (ET-1, ET-2 and ET-3) [1,2]. ET-1 is a potent vasoconstrictor produced by endothelial cells that also induces mitogenesis in vascular smooth muscle cells [1,3]. Two major types of ET receptors, termed endothelin receptor type A (ETA) and endothelin receptor type B (ETB) have been identified, cloned and sequenced in mammals [4,5]. The ETA receptor mediates most of the vasoconstrictor action of ET-1 and has selective affinity for . The ETB receptor has equal affinities for all ET isoforms and has been shown to release endothelium-derived nitric Abstract Aims/hypothesis. The endothelin system (ET system) has been implicated in the retinal blood flow abnormalities that precede the onset of diabetic retinopathy. This study was undertaken to assess whether the density and localisation of both the immunoreactive endothelin-1 and endothelin receptors in rat retina change in the early stages of diabetes and the insulin treatment would affect those changes. Methods. Untreated streptozotocin-diabetic, insulintreated streptozotocin-diabetic and age-matched control rats were killed 15, 45 and 90 days after the induction of diabetes. Binding assays were used to determine the density and proportion of endothelin receptors in neural retinal membranes. Localisation of endothelin receptors and immunoreactive endothelin-1 were analysed by microautoradiography and immunohistochemistry, respectively. Results. Fifteen days after the induction of diabetes, the neural retinal membranes of untreated streptozotocin-diabetic rats showed a statistically significant decrease in the density of both endothelin receptor subtypes when compared with age-matched control rats. At 90 days, however, the density of endothelin receptors type B was statistically significantly higher than that of control rats, and the innermost layers of the diabetic retina also showed an increase of both endothelin receptor type B receptor and immunoreactive endothelin-1 signal. Insulin treatment during 90 days up-regulated endothelin receptor type A in neural retinal membranes and in the innermost layers of the retina when compared with control retinas. Conclusion/interpretation. These results show that the endothelin system is altered in both vascular and neuronal components of the retina in early diabetic retinopathy. The up-regulation of endothelin receptor type A induced by insulin treatment suggests that insulin might be involved in retinal microangiopathy. [Diabetologia (2000) 43: 773±785]

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Section: Discussionsupporting

confidence: 90%

“…We have previously reported the presence of ETA and ETB binding sites in neural retinal membranes [11]. On the other hand, ETA and ETB mRNA expression has been detected in the rat retina [13], and autoradiographic studies have shown that ETA and ETB receptors are present in the retinal blood vessels and the neural retina of human and rabbit eyes [16].…”

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confidence: 95%

Changes in the density and localisation of endothelin receptors in the early stages of rat diabetic retinopathy and the effect of insulin treatment

et al. 2000

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“…The ET-1 receptors (ET A and ET B ) belong to the family of G-protein-coupled receptors. 50 Within ocular tissues, ET A and ET B are constitutively expressed in human uveal tissues, 51 the retina, and ONH. 52 ET A is mainly present on the vascular smooth cells and is responsible for the vasoconstriction caused by ET-1, and ET B is mainly present on the vascular endothelium and is believed to produce transient vasodilatation through release of NO.…”

Section: Discussionmentioning

confidence: 99%

Black Currant Anthocyanins Normalized Abnormal Levels of Serum Concentrations of Endothelin-1 in Patients with Glaucoma

Yoshida

Ohguro

2013

Journal of Ocular Pharmacology and Therapeutics

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Purpose: Our recent study, which involved a randomized, placebo-controlled, double-masked 24-month trial (Ophthalmologica 2012;228:26-35), revealed that oral administration of black currant anthocyanins (BCACs) slowed down the visual field deterioration and elevation of ocular blood flow of open-angle glaucoma (OAG). To elucidate the underlying mechanisms of these BCAC-induced effects, as possible factors affecting glaucomatous optic neuropathy, changes of serum endothelin-1 (ET-1), nitric oxide (NO), and antioxidative activities were examined in the present study. Methods: From among patients with OAG who participated in the randomized, placebo-controlled, doublemasked trial, serum specimens were obtained from BCAC-treated (n = 19) or placebo-treated (n = 19) patients at baseline and every 6 months. Healthy volunteers (n = 20) with age and gender matching the patients were used as a control. Serum ET-1 concentration, [NO 2 -] and [NO 2 -+ NO 3 -] levels, advanced oxidation protein products (AOPP), and antioxidant activities were measured by using commercially available kits. Results: At the trial baseline, serum ET-1 concentrations were significantly lower in patients with OAG (BCACs, 3.18 -1.06 pg/mL; placebo, 3.44 -0.84 pg/mL) than those in healthy volunteers (4.38 -1.03 pg/mL) (one-way analysis of variance and a Tukey's multiple comparison post hoc test, P < 0.05). Upon administration of BCACs, serum ET-1 concentrations increased to the levels of those in healthy volunteers during the 24-month period. In contrast, those of placebo-treated patients remained at lower levels (3.82 -1.14 pg/mL). While [NO 2 -] and [NO 2 -+ NO 3 -] levels, AOPP, and antioxidative activities of patients from both the BCACs and placebo groups showed comparable levels to those of healthy subjects at baseline, no significant changes were observed during the observational period in either the BCAC or placebo groups. Conclusions: Among the possible beneficial effects of BCACs toward visual field progression in patients with OAG, our present results suggest that BCACs caused normalization of serum ET-1 levels, and this may modulate ET-1-dependent regulation of the ocular blood hemodynamics.

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“…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.…”

Section: Introductionmentioning

confidence: 99%

Calcium Dobesilate Prevents Neurodegeneration and Vascular Leakage in Experimental Diabetes

Solà-Adell

Bogdanov

Hernández

et al. 2017

Current Eye Research

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Purpose: The mechanisms involved in the reported beneficial effects of Calcium dobesilate monohydrate (CaD) for the treatment of diabetic retinopathy (DR) remain to be elucidated. The main aim of the present study is to examine whether CaD prevents early events in the pathogenesis of DR such as neurodegeneration and vascular leakage. In addition, putative mediators of both neurodegeneration (glutamate/GLAST, ET-1/ETB receptor) and early microvascular impairment (ET-1/ETA receptor, oxidative stress, VEGF, and the PKC-delta-p38 MAPK pathway) have been examined. Methods: Diabetic (db/db) mice were randomly assigned to daily oral treatment with CaD (200 mg/Kg/ day) (n = 12) or vehicle (n = 12) for 14 days. In addition, 12 non-diabetic (db/+) mice matched by age were used as the control group. Functional abnormalities were assessed by electroretinography. Neurodegeneration and microvascular abnormalities were evaluated by immunohistochemistry and Western blot. Glutamate was determined by HPLC. Results: CaD significantly decreased glial activation and apoptosis and produced a significant improvement in the electroretinogram parameters. Mechanistically, CaD prevented the diabetes-induced upregulation of ET-1 and its cognate receptors (ETA-R and ETB-R), which are involved in microvascular impairment and neurodegeneration, respectively. In addition, treatment with CaD downregulated GLAST, the main glutamate transporter, and accordingly prevented the increase in glutamate. Finally, CaD prevented oxidative stress, and the upregulation of VEGF and PKC delta-p38 MAPK pathway induced by diabetes, thus resulting in a significant reduction in vascular leakage.Conclusions: Our findings demonstrate for the first time that CaD exerts neuroprotection in an experimental model of DR. In addition, we provide first evidence that CaD prevents the overexpression of ET-1 and its receptors in the diabetic retina. These beneficial effects on the neurovascular unit could pave the way for clinical trials addressed to confirm the effectiveness of CaD in very early stages of DR. ARTICLE HISTORY

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Endothelin Receptor-Binding Subtypes in the Human Retina and Choroid

Cited by 69 publications

References 28 publications

Changes in the density and localisation of endothelin receptors in the early stages of rat diabetic retinopathy and the effect of insulin treatment

Changes in the density and localisation of endothelin receptors in the early stages of rat diabetic retinopathy and the effect of insulin treatment

Black Currant Anthocyanins Normalized Abnormal Levels of Serum Concentrations of Endothelin-1 in Patients with Glaucoma

Calcium Dobesilate Prevents Neurodegeneration and Vascular Leakage in Experimental Diabetes

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