Angiotensin II and Its Receptor Subtypes in the Human Retina

Abstract

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...

Angiotensin II Type 1 Receptor Signaling Contributes to Synaptophysin Degradation and Neuronal Dysfunction in the Diabetic Retina

“…Since ERK is known to be one of AT1R's signaling pathways, the present data are compatible with clinical (5,7,28,29) and experimental (4) studies showing increased angiotensin II generation in the diabetic eye. The cellular source of angiotensin II was shown to be retinal glial cells by immunohistochemistry for human postmortem eyes (30). In the liver and kidney as well (31)(32)(33), diabetes-induced activation of the RAS causes elevated concentration of tissue angiotensin II.…”

Regulation of angiotensin II receptors and extracellular matrix turnover in human retinal pigment epithelium: role of angiotensin II

“…On the other hand, the signaling mechanisms of the AT2 receptor are diverse, and only a few of them have been characterized (17). Although ANG II receptor expression has been confirmed in the retinal vasculature (22, 63), retina (5, 62, 75), and the pigment epithelium-choroid complex (65,67), nothing is known about the regulation of ANG II receptor subtype expression and their function in the RPE, which is a cell type of pivotal importance in the progression of AMD (25).Among its many actions, ANG II promotes interstitial extracellular matrix (ECM) turnover by regulation of the ECM proteins (12,20,33,66,70,73,74,77). For example, ANG II has been shown to stimulate synthesis of fibronectin, collagen, tissue inhibitor of metalloproteinase (TIMP)-2, and matrix metalloproteinase (MMP)-2 in mesangial and proximal tubule cells through activation of transforming growth factor-␤ secretion (62,27).…”

“…On the other hand, the signaling mechanisms of the AT2 receptor are diverse, and only a few of them have been characterized (17). Although ANG II receptor expression has been confirmed in the retinal vasculature (22,63), retina (5,62,75), and the pigment epithelium-choroid complex (65,67), nothing is known about the regulation of ANG II receptor subtype expression and their function in the RPE, which is a cell type of pivotal importance in the progression of AMD (25).…”

Up-Regulation of Renin-Angiotensin System in Diabetes and Hypertension: Implications on the Development of Diabetic Nephropathy

“…Another relevant change in our understanding of the classical endocrine RAS was the description of all components of the system in several tissues, including kidney, heart, brain, pancreas, adrenal, reproductive aparatus, retina, liver, gastrointestinal tract, lung and adipocytes, leading to the identification of new roles for angiotensins as paracrine and autocrine/intracrine function (Bataller et al;Danser & Schalekamp, 1996;Lavoie & Sigmund, 2003;1994;Paul et al;2006;Ribeiro-Oliveira Jr et al;Senanayake et al;. RAS tissue appears to be regulated independently of the systemic one, and has been shown to contribute to a great number of homeostatic pathways, including cellular growth, vascular proliferation, extracellular formation and apoptosis (Paul et al;2006), via its specific receptors, such as AT1R, AT2R, prorenin/renin [(P)RR], Mas and also Ang III and IV receptors ( Figure 3) (Nguyen et al 2002;.…”