The Interaction between the Renin-Angiotensin System and Vascular Endothelial Growth Factor in the Pathogenesis of Retinal Neovascularization in Diabetes

Wilkinson-Berka, Jennifer L.; Kelly, Darren J.; Gilbert, Richard E.

doi:10.1159/000051088

Cited by 21 publications

(16 citation statements)

References 84 publications

(101 reference statements)

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“…Ang II has powerful angiogenic actions. 66,98 Ang II is associated with overexpression of angiogenic factors such as VEGF 13,16,99,100 and Ang 2 that have an important role in the development of retinal neovascular- ization, 101-103 a characteristic feature of PDR. PDR is characterized by the ingrowth of new blood vessels into the retina and vitreous that eventually results in impaired vision and blindness.…”

Section: 69mentioning

confidence: 99%

Angiotensin II and Its Receptor Subtypes in the Human Retina

Senanayake

Drazba

Shadrach

et al. 2007

Invest. Ophthalmol. Vis. Sci.

214

156

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PURPOSE.To quantify and evaluate the distribution of angiotensin II (Ang II) and its receptors in the human retina. METHODS. Donor eyes were obtained within 12 hours postmortem and classified as hypertensive or normotensive and diabetic or nondiabetic, based on the donors' medical histories. Ang II in retina and vitreous was quantified by RIA. Ang II receptors were characterized and quantified by competitive membrane-binding assays. Ang II, its heptapeptide metabolite Ang-(1-7), and AT1 and AT2 receptors were localized by immunohistochemistry and confocal imaging. RESULTS. Levels of Ang II in the retina were significantly higher than in vitreous (P Ͻ 0.05). Ang II in the diabetic retina had a higher median compared with that in the nondiabetic retina. Ang II and Ang-(1-7) colocalized in retinal Müller cells. The retina had the highest levels of Ang II receptors that were significantly higher than the optic nerve, retinal pigment epithelium-choroid complex, and ciliary body-iris complex (P Ͻ 0.05). AT1 receptors were more abundant than AT2 receptors in the retina. Immunoreactivity for AT1 was detected in Müller cells and on blood vessels. AT2 receptors were localized throughout the Müller cells and nuclei of ganglion cells and neurons in the inner nuclear layer. CONCLUSIONS. In the human retina, identification of Ang II and its bioactive metabolite Ang-(1-7) in Müller cells suggests that these glial cells are able to produce and process Ang II. Ang receptors were localized in the blood vessels and neural cells. Local Ang II signaling may thus allow for autoregulation of neurovascular activity. Such an autonomous system could modulate the onset and severity of retinovascular disease. (Invest Ophthalmol Vis Sci. 2007;48:3301-3311) DOI:10.1167/iovs.06-1024 D iabetic retinopathy is one of the major complications of diabetes mellitus and the leading cause of visual loss and blindness in the adult population of the United States. It has been viewed as a disorder of the retinal vasculature 1,2 ; however, evidence from numerous reports indicate that neural function of the retina is compromised before the vascular lesions are clinically diagnosed. At the cellular level, diabetes alters the structure and function of most cell types.3-9 Many factors have been implicated in the pathogenesis of diabetic retinopathy. Clinical and experimental studies have shown that the renin-angiotensin system (RAS) plays a pivotal role in the progression of the disease, presumably through local changes in blood flow and production of vascular endothelial growth factor (VEGF 10 -22 ). Furthermore, Ang II may act as an inflammatory agent by enhancing vascular permeability through prostaglandins and VEGF 23 and contribute to the recruitment of inflammatory cells by inducing chemokines and adhesion molecules. 23,24 Although an independent RAS has not been established in the retina, many reports support the concept of a paracrine RAS in this organ. [25][26][27][28] In the classic pathway, Ang II is produced by the sequential processing of plasma...

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Section: 69mentioning

confidence: 99%

Angiotensin II and Its Receptor Subtypes in the Human Retina

Senanayake

Drazba

Shadrach

et al. 2007

Invest. Ophthalmol. Vis. Sci.

214

156

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“…Moreover, several biochemical mediators implicated in the pathogenesis of diabetic retinopathy have been demonstrated to increase the expression of VEGF, including glucose, advanced glycation products, adenosin, cytokines (transforming growth factor-β, interleukin-1) and numerous growth factors (fibroblast growth factor and pigment-epithelium-derived growth factor, platelet-derived growth factor, insulin-like growth factor-1, transforming growth factor-β) [19, 20, 21, 23, 82, 83, 105, 108, 120]. High numbers of glycation end products, for example, have been seen in the blood of patients with diabetic retinopathy, and this increase is believed to be a stimulator of VEGF release and then a causal factor in the development of diabetic retinopathy [112].…”

Section: Hypothetical Pathogenesis Of Pdvrmentioning

confidence: 99%

“…Also, this factor favors an inhibitory environment when oxygen concentrations are normal or high [26]. Then, pigment-epithelium-derived growth factor plays a considerable role in protecting the retina from pathological angiogenesis [120]. The production of pigment-epithelium-derived growth factor is downregulated by hypoxia, which is the central pathogenic stimulus of VEGF-A.…”

Section: Hypothetical Pathogenesis Of Pdvrmentioning

confidence: 99%

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Pathogenesis and Classification of Proliferative Diabetic Vitreoretinopathy

Kroll¹,

Rodrigues²,

Hoerle³

2007

Ophthalmologica

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Purpose: To review the current knowledge regarding the pathogenesis of proliferative diabetic vitreoretinopathy (PDVR) and to present recommendations for its clinical staging. Design: Focused literature review and authors’ clinical experience. Results: Although several biochemical mediators may be responsible for the pathogenesis of PDVR, no common biochemical pathway exists. Of those mediators, vascular endothelial growth factor is the one most studied so far. However, since in proliferative diabetic retinopathy (PDR) the thickened posterior vitreous cortex is one of the main factors in the development of proliferations, a consequent shrinkage of the posterior vitreous cortex leads to hemorrhages and tractive retinal detachments. Therefore, PDR should be called PDVR. In consequence, the authors present a new morphological classification of PDVR. Conclusions: There is no consensus about the biochemical pathway responsible for the progression of PDVR. Although several classifications are described in the literature, the classification suggested here is important in the judgment of, the communication about and the therapy of diabetic retinopathy. Furthermore, it is the only reliable classification for predicting the surgical outcome in diabetics.

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“…The right ovary from each rat was collected in 300 µl of 0·1 M PBS (pH 7·4) and snap-frozen in liquid N 2 for analysis of total renin content using established techniques (Berka et al 1995, Kelly et al 1998, Wilkinson-Berka et al 2001. The left ovary was collected in 300 µl of 0·1 M PBS (pH 7·4) with protease inhibitors (7·5 mM N-ethylmaleimide, 6 mM disodium ethylenediamine tetraacetic acid and 30 mM benzamidine) and snap-frozen in liquid N 2 for analysis of active renin content.…”

Section: The Cellular Localisation Of the Ovarian Ras In Untreated Htmentioning

confidence: 99%

Angiotensin II influences ovarian follicle development in the transgenic (mRen-2)27 and Sprague-Dawley rat

Gooyer¹,

Skinner²,

Wlodek³

et al. 2004

Journal of Endocrinology

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There is accumulating evidence that local reninangiotensin systems (RASs) influence cell growth and organ function in a variety of tissues including the ovary. The first aim of this study was to characterise the cellular location of RAS components in the rat ovary. This was facilitated by the use of the hypertensive transgenic (mRen-2)27 rat which overexpresses renin and angiotensin in extra-renal tissues. Comparisons were made with normal Sprague-Dawley (SD) rats. The second aim was to determine if the upregulated RAS of the transgenic (mRen-2)27 rat and infusion of angiotensin II (ANG II) in SD rats influences follicle number and litter size. Gene expression, immunohistochemical and autoradiographic techniques were used to identify a discrete RAS including ANG II receptors in the ovarian stroma, follicles (particularly atretic) and to a lesser extent corpora lutea. The RAS at these sites was most abundant in homozygous (HMZ) followed by heterozygous (HTZ) (mRen-2)27 rats and then SD rats. Large antral and preovulatory follicles and litter size were reduced in (mRen-2)27 rats. In HMZ (mRen-2)27 rats and SD rats infused with ANG II, angiotensin 1a (AT 1a ) receptor mRNA in the ovarian stroma was lower than control SD rats and was associated with a reduction in large antral and preovulatory follicles. These findings indicate that upregulation of the ovarian RAS in the rat influences follicular development and, potentially, reproductive capacity.

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The Interaction between the Renin-Angiotensin System and Vascular Endothelial Growth Factor in the Pathogenesis of Retinal Neovascularization in Diabetes

Cited by 21 publications

References 84 publications

Angiotensin II and Its Receptor Subtypes in the Human Retina

Angiotensin II and Its Receptor Subtypes in the Human Retina

Pathogenesis and Classification of Proliferative Diabetic Vitreoretinopathy

Angiotensin II influences ovarian follicle development in the transgenic (mRen-2)27 and Sprague-Dawley rat

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