Augmented retinal endothelin-1, endothelin-3, endothelinA and endothelinB gene expression in chronic diabetes

Chakrabarti, Subrata; Gan, Xiaohong Tracey; Merry, Andrew; Karmazyn, Morris; Sima, Anders A. F.

doi:10.1076/ceyr.17.3.301.5216

Cited by 59 publications

(52 citation statements)

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“…Furthermore, in the time period between 15 and 90 days, we have observed a statistically significant increment of the density of ETB receptors in the neural retinal membranes of the untreated STZ-diabetic rats. In contrast, an increase of both ETA and ETB mRNAs has been reported in the whole retina of 6-month-old spontaneously diabetic BB/W rats compared with age-matched control rats [13]. This discrepancy is possibly due to the different animal model and age and to the simultaneous analysis of both vascular and neuronal ET receptors in that author's study.…”

Section: Discussioncontrasting

confidence: 50%

“…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: 99%

“…In the retina, immunoreactive ET-1 (IR-ET-1), and ET-3 (IR-ET-3) have been found in human, rat, and rabbit retinal extracts [10±12], and ET-1 and ET-3 mRNA expression has been detected in the whole rat retina [13]. Immunoreactive ET-1 has been localised in the different layers of human and rat retina [14,15].…”

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confidence: 99%

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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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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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“…We and others have shown that ETs in the retina are upregulated in diabetes, including demonstrating increased immunoreactivity of ET-1 and ET-3 as well as increased ET and ET receptor gene expression in retinal tissues in chronically diabetic BB/W rats (18,(20)(21)(22). We have further shown that galactose feeding-and diabetes-induced early vasoconstriction in the retina was prevented by an ET receptor antagonist (23,24).…”

Section: Endothelin Receptor Blockade Prevents Augmented Extracellulamentioning

confidence: 59%

Endothelin receptor blockade prevents augmented extracellular matrix component mRNA expression and capillary basement membrane thickening in the retina of diabetic and galactose-fed rats.

et al. 2000

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Endothelins (ETs) are a family of vasoactive peptides that have mitogenic properties and have also been associated with altered long-term nuclear signaling. We have previously shown that mRNA levels for ET-1 , E T-3, and their receptors are upregulated under hyperhexosemic conditions. In this study, an endothelin antagonist was used to assess the effects of endothelin blockage on the production of two basement membrane transcripts, fibronectin and collagen 1 (IV). The microvascular basement membranes were analyzed using ultrastructural morphometry. Streptozotocin-induced diabetic rats, galactose-fed rats (30% galactose in diet), and nondiabetic, non-galactose-fed control rats were studied after 1-month and 6-month follow-up. Simultaneously, similar animal groups were treated with a general ET receptor blocker (bosentan, 1 0 0 m g · k g -1 · day -1 ) and investigated. Semiquantitative reverse transcription-polymerase chain reaction for fibronectin and collagen 1 (IV) was conducted after 1 month of follow-up with comparison to -a c t i n housekeeping gene using slot blot hybridization and d e n s i t o m e t r y. Basement membrane thickness was assessed after 6 months of follow-up in diabetic rats, using the orthogonal intercept method. After 1 month of follow-up, increased fibronectin and collagen 1 (IV) mRNA were present in the retina of diabetic and galactosemic animals, and the bosentan-treated groups exhibited mRNA levels similar to the control animals. After 6 months of follow-up, diabetes and galactose feeding induced basement membrane thickening, which was partially prevented by bosentan treatment. The above findings indicate that increased production of extracellular matrix proteins leading to thickening of microvascular basement membrane, secondary to hyperhexosemia, may be mediated via augmented ET production. D i a b e t e s 4 9 :6 6 2-666, 2000

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“…It is likely that an increase in endogenous expression of ET-1 and ET-3 contributes to the reduction of retinal blood flow reported in the early stages of diabetes. 124 Inadequate blood flow, hypoxia and hypercapnia potentiate the production of NO and adenosine which relaxes pericytes and smooth muscle cells.22 It has been suggested that these two agents normally maintain the retinal vasculature in a tonic state of mid-dilatation. The precise biochemical events leading to alteration in the release of vasoactive substances in hyperglycaemia are still ill-understood; however, it has recently been proposed that elevated DAG and the resultant sustained activation of PKC-f3II in hyperglycaemia represents a major causative factor in the abnormal retinal haemodynamics in diabetic rats.…”

Section: Blood Flow Alterationsmentioning

confidence: 99%

Diabetic retinopathy: Some cellular, molecular and therapeutic considerations

Archer

1999

Eye

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Augmented retinal endothelin-1, endothelin-3, endothelinA and endothelinB gene expression in chronic diabetes

Abstract: These findings indicate that retinal ET-1, ET-3, ET(A) and ET(B) mRNA expression in increased in the chronically diabetic BB/W rat. Augmented gene expression of ETs and their receptors potentially may be of importance in the pathogenesis of retinal microangiopathy in diabetes.

Cited by 59 publications

References 25 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

Endothelin receptor blockade prevents augmented extracellular matrix component mRNA expression and capillary basement membrane thickening in the retina of diabetic and galactose-fed rats.

Diabetic retinopathy: Some cellular, molecular and therapeutic considerations

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