The retinal renin–angiotensin system: Roles of angiotensin II and aldosterone

Abstract

In the present review we examine the experimental and clinical evidence for the presence of a local renin–angiotensin system within the retina. Interest in a pathogenic role for the renin–angiotensin system in retinal disease originally stemmed from observations that components of the pathway were elevated in retina during the development of certain retinal pathologies. Since then, our knowledge about the contribution of the RAS to retinal disease has greatly expanded. We discuss the known functions of the renin–angiotensin system in retinopathy of prematurity and diabetic retinopathy. This includes the promotion of retinal neovascularization, inflammation, oxidative stress and neuronal and glial dysfunction. The contribution of specific components of the renin–angiotensin system is evaluated with a particular focus on angiotensin II and aldosterone and their cognate receptors. The therapeutic utility of inhibiting key components of the renin–angiotensin system is complex, but may hold promise for the prevention and improvement of vision threatening diseases.

Introduction

In the classical renin–angiotensin system (RAS), prorenin is activated to form renin in juxtaglomerular cells of the kidney (Fig. 1). Renin then binds to the liver-produced angiotensinogen to generate the decapeptide angiotensin I (Ang I; 1–10), which is then hydrolysed by angiotensin converting enzyme (ACE), which may be present in circulation or locally within tissues, to produce the oligopeptide angiotensin II (Ang II, 1–8). By binding to the type 1 angiotensin receptor (AT1R), Ang II is the predominant physiological regulator of blood pressure and is one of the major targets of pharmacological intervention for the treatment of hypertension [117], [120]. Ang II acting via the AT1R is also known to have important roles in the promotion of cellular pathology including apoptosis, hypertrophy, neovascularization, inflammation and fibrosis that may be dependent or independent of its effects on blood pressure [9], [67], [98], [110], [135]. Ang II also triggers the release of aldosterone from the adrenal cortex (Fig. 1). The binding of aldosterone to the mineralocorticoid receptor (MR) contributes to electrolyte and water balance in the body and can also influence heart, kidney and vascular pathology [38], [122]. Cross-talk between Ang II and aldosterone may also potentiate the signaling pathways that are activated by each agent [55], [87].

The RAS is now considered to be far more complex than this classical view of the pathway. Prorenin and renin may also bind to the (pro)renin receptor [(P)RR] [76]. Binding to the (P)RR can elicit angiotensin-independent actions via the activation of promyelocytic zinc finger, protein phosphatidylinositol-3 kinase and mitogen activated protein kinases to influence cellular proliferation and apoptosis [99], [100]. The antagonism of the AT1R within the cascade also requires consideration. Ang I can be cleaved to Ang 1–7, via the ACE homologue, ACE2, or neutral endopeptidase. Ang 1–7 may stimulate the Mas receptor to partially antagonize the effects of the AT1R by promoting vasodilation, the release of nitric oxide and phosphorylation of Akt [25], [118]. Similarly, the binding of Ang II to the type 1 angiotensin receptor (AT2R) has been reported to oppose the actions of the AT1R [54], [88].

The retina is a complex structure involving close anatomical connections between the microvasculature and various types of neurons and glia. The vision threatening pathology that develops in retinal diseases such as retinopathy of prematurity (ROP) and diabetic retinopathy involves changes to the microvasculature (e.g. apoptosis, neovascularization, leakage) as well as glial and neuronal dysfunction. Over the past 20 years, information has accumulated that clearly demonstrates the presence of a local RAS in the retina with components most abundantly expressed on retinal microvessels, glia (e.g. macroglial Müller cells) and neurons (ganglion cells). Components of the RAS have also been identified in other ocular structures such as the choroid and ciliary body. The cellular localization of RAS components in the eye is detailed in Table 1.

In 1996 we reported prorenin and renin to be expressed in Müller cells [10], a macroglial cell that expands almost the entire width of the retina, and closely interacts with the inner retinal microvasculature. Müller cells are viewed to contribute to the neovascularization of ROP and diabetic retinopathy by providing a source of the potent angiogenic and permeability factor, vascular endothelial growth factor (VEGF) [85], [126]. Müller cells also contribute to the formation of epiretinal membranes that can develop in severe diabetic retinopathy [15]. Other components of the RAS including ACE, ACE2, Ang 1–7, Ang II and AT1R, have also been localized to retinal Müller cells in a variety of species [28], [51], [102], [119], [129]. Other retinal glia such as astrocytes and microglia have been reported to express RAS components (Table 1). With respect to neurons, almost all components of the RAS have been localized to ganglion cells, which are located at the retinal surface and are involved in ROP via their increased production of VEGF in response to retinal hypoxia [45]. Ganglion cells may degenerate in ROP and diabetic retinopathy to contribute to an overall decline in retinal function [50]. Some RAS components are also expressed in other retinal neurons such as amacrine cells, bipolar cells and photoreceptors (Table 1). Endothelial cells and pericytes of the retinal microvasculature also contain RAS components. Until recently, studies of the retinal RAS have largely focused on the cellular location of Ang II and earlier parts of the RAS pathway. Emerging evidence indicates that a local aldosterone system may exist in the retina, with our report of aldosterone synthase mRNA in whole retina, glia and ganglion cells [24], [133], and the MR located on vascular cells (endothelial cells and pericytes), ganglion cells, glia and retinal pigment epithelium [24], [133]. The presence of 11β-hydroxysteroid dehydrogenase 2 in certain retinal cell types suggests that aldosterone rather than cortisol may influence MR's actions in retina [24], [144].

The impetus for the study of the role of the RAS in the retina was arguably due to observations that components of the pathway were elevated in situations of retinal pathology. For instance, prorenin, renin, ACE and Ang II are increased in the plasma and eyes of individuals with diabetic retinopathy [21], [48], [102], [140] and ROP [139], and in experimental models of these diseases [67], [68]. To date, most studies evaluating a causal role for the RAS in retinopathy have focused on the microvasculature, given that retinal vascular pathology is a major contributor to vision loss. There is evidence that Ang II and aldosterone influence both endothelial cells and pericytes in the retinal microvasculature. In cultured retinal endothelial cells, Ang II modulates both survival and proliferation. For instance, Ang II induced retinal endothelial cell apoptosis [66] and reduced the expression of pigment epithelium derived growth factor mRNA, an anti-angiogenic factor in the retina [133]. Both Ang II and aldosterone have mitogenic effects on retinal endothelial cells [79], [80], [133], and Ang II has been reported to enhance VEGF-stimulated endothelial cell proliferation, which involves angiopoeitin2, Tie2 and protein kinase C [79], [80]. Furthermore, the administration of aldosterone resulted in the exacerbation of pathological neovascularization in experimental ROP [133], and retinal swelling and activation of Müller cells in rats [144].

The direct effects of Ang II on the retinal microvasculature have perhaps best been studied in retinal pericytes. Pericytes are considered to be the vascular smooth muscle cell counterpart for microvessels, and thereby are implicated in the regulation of capillary tone [136]. Pericytes may have additional functions including the maintenance of microvascular homeostasis [136]. For example, in diabetes their demise is considered to be an early sign of diabetic retinopathy. There is convincing evidence that Ang II directly influences retinal pericytes, by uncoupling them from the microvasculature, via the activation on non-specific cation and calcium-activated chloride channels [49], [143]. Tissue culture studies have revealed that via the AT1R, Ang II can stimulate pericyte migration which involves both transforming growth factor-β and platelet derived growth factor (PDGF) [70], [71]. Additionally, Ang II can also influence pericyte survival, by augmenting pericyte apoptosis, which may involve the advanced glycation end-product pathway [66], [137]. Overall, it is clear that Ang II influences the retinal microvasculature, and emerging evidence suggests similar effects of aldosterone. The effects of Ang II, prorenin and aldosterone and their cognate receptors on non-vascular cells in the retina, however, require further elucidation.