The renin–angiotensin system in retinal health and disease: Its influence on neurons, glia and the vasculature☆
Introduction
Recognized as one of the oldest phylogentic hormone systems, the Renin–Angiotensin System (RAS) is vital for the control of systemic blood pressure, salt appetite and aldosterone formation (Paul et al., 2006). In addition to the systemic effects of a RAS, many organs express components of the RAS, indicative of local tissue angiotensin-formation system (Downie et al., 2009, Paul et al., 2006, Senanayake et al., 2007, Wheeler-Schilling et al., 1999). Over the last 20 years there has been emerging evidence that all components of the RAS are expressed within the retina and that angiotensin II (Ang II), the main effector peptide of the RAS, regulates retinal function. Moreover, dysregulation of the RAS has been implicated in retinal vascular diseases such as retinopathy of prematurity and diabetic retinopathy. In particular, agents that inhibit the RAS prevent the development of a variety of pathological effects in animal models and patients with diabetic retinopathy. The aim of this review is to describe what is known about the influence of the RAS in both normal and pathological retinal conditions, with a particular emphasis on the role of the RAS on neurovascular events in the retina.
The actions of the peptides involved in both the local retinal and systemic RAS are summarized in Fig. 1. The major source of circulating Ang II is the juxtaglomerular cells of the kidney which synthesize both the enzyme, renin, and its precursor, prorenin. Angiotensinogen is the sole substrate for renin, and is primarily formed in the liver. Renin acts to liberate angiotensin I (Ang I) from angiotensinogen (Fig. 1). Ang I is then converted to Ang II by the zinc metalloprotease angiotensin converting enzyme (ACE), which is highly expressed in pulmonary endothelial cells and other vascular sites. The main cellular effects of Ang II are mediated by two receptors that belong to the superfamily of seven trans-membrane G-protein coupled receptors, Ang II type 1 receptor (AT1R) and Ang II type 2 receptors (AT2R) (Stroth and Unger, 1999), although other receptors for Ang II have been identified (Paul et al., 2006, Wright and Harding, 1997). Both receptor types display similar binding affinity for Ang II (Timmermans et al., 1993). Most biological effects of Ang II are thought to be mediated by activation of AT1R, and include smooth muscle and pericyte contraction and the promotion of cell growth and angiogenesis (Kawamura et al., 2004, Otani et al., 1998b). AT1Rs are widely distributed throughout many tissues, including the heart, brain, kidneys and eye (Downie et al., 2009, Paul et al., 2006, Senanayake et al., 2007, Wheeler-Schilling et al., 1999). The actions of the AT2R are not completely understood, but may oppose some actions of AT1Rs (Chung et al., 1998). AT2Rs are abundantly expressed in foetal and developing tissues and then recede after birth (Alcorn et al., 1996, Cook et al., 1991, Grady et al., 1991). This phenomenon has been interpreted to reflect the potential involvement of AT2Rs in neuronal differentiation and plasticity (Millan et al., 1991). In addition, the stimulation of cerebral AT2Rs has been shown to protect against ischaemic-induced injury, by supporting neuronal survival and neurite outgrowth (Li et al., 2005). Over the past few years, other members of the RAS including prorenin, the (pro)renin receptor and ACE2, have been identified in eye and some implicated in the development of retinal disease (Senanayake et al., 2007, Tikellis et al., 2004).
Various parts of the eye express the components of the RAS, suggesting that the eye contains an Ang II formation system that is separate to that functioning systemically. The importance of the RAS in retinal function has been implied from the large number of studies demonstrating positive effects when inhibitors of ACE or antagonists to AT1R are used in the treatment of retinal diseases, such as diabetic retinopathy or retinopathy of prematurity. However, the specific mechanisms by which dysregulation of the RAS causes retinal vascular disease are not well understood. Here, we will first summarize what is known about the retinal RAS and how it influences retinal glia, neurons and the vasculature. We will describe in more detail how the RAS influences retinal development, especially retinal vascular development. Finally, we will examine what is known about the RAS in retinal vascular diseases.
Section snippets
The renin–angiotensin system in the normal retina
It is now well established that all components of the RAS are expressed by the cells within the retina including angiotensinogen, prorenin, renin, and Ang I and II (Berka et al., 1995b, Danser et al., 1994, Danser et al., 1989a). Evidence for a retinal specific Ang II formation system that is independent of the systemic RAS comes from the observations that there is a large difference in concentration of Ang II, prorenin and renin in the retina compared with the plasma. Ang II does not cross the
The role of angiotensin in the formation and growth of retinal blood vessels
One of the main functions of the RAS systemically is the regulation of the vasculature, especially for the control of systemic blood pressure (Paul et al., 2006). In the retina, Ang II is an important regulator of vascular function and also plays important roles in the formation and development of the retinal vasculature.
The development of retinal blood vessels involves two distinct, but complementary mechanisms: vasculogenesis and angiogenesis (Murphy et al., 1991). Vasculogenesis refers to
Role of renin–angiotensin system in normal retinal development
Neuro-active peptides have been shown to influence the development of the CNS (Gonzalez et al., 1997, Pincus et al., 1990) and there is evidence that Ang II modulates both cell growth and survival in several tissues (Lucius et al., 1999). In the brain, AT2R receptors are known to be expressed at high levels during foetal and early postnatal life, but have greatly reduced levels in adult tissue. Moreover, Ang II has been shown to increase the differentiation of mesencephalic neural precursors
The role of the renin–angiotensin system in retinal vascular disease
In addition to its proposed physiologic roles, Ang II may play a major role in the pathogenesis of retinal vascular disease. There is considerable evidence that dysregulation of the RAS may play a role in the aetiology of retinal vascular diseases and that blockade of the action of Ang II prevents or slows disease progression (Wilkinson-Berka and Fletcher, 2004). In this section we summarize the evidence showing that blockade of the RAS reduces vascular, glial and neuronal changes in
Dysregulation of the RAS and age-related macular degeneration
Age-related Macular degeneration (AMD) is a leading cause of visual impairment, especially in those in the older generation. It is recognized to consist of two main forms, both of which are linked with vision loss. Dry or atrophic forms of AMD are associated with significant loss of photoreceptors, whilst the wet form is linked with pathological growth of choroidal blood vessels that break through Bruch’s membrane to populate the overlying retina.
There are several ways that dysregulation of the
Future directions
Although there is considerable evidence for a role for Angiotensin II in regulating both normal retinal function and in retinal vascular diseases, a great deal more is required before a complete understanding of the mechanisms involved is gained. In view of the importance of the RAS in controlling systemic blood pressure, it is often difficult to ascribe a functional role for angiotensin II independent on its systemic effects. Moreover, the importance of other members of the RAS, such as
Conclusion
In conclusion, Ang II has important roles in modulating normal retinal function and also in exacerbating retinal disease. It is becoming apparent that the retina has its own independent Ang II formation system, that may be important for regulating neuronal, glial and the retinal vasculature. Ang II is implicated in retinal angiogenesis, and has a role in the development of the normal retinal vasculature. However, the mechanisms by which Ang II is involved in retinal vascular disease are less
Acknowledgements
The work described in this review has been supported by the grants from the National Health and Medical Research Council of Australia, The Juvenile Diabetes Research Foundation and Diabetes Australia Research Trust. We would also like to sincerely thank the extraordinary efforts of our laboratory members both past and present who have contributed in various ways to the work that is described here.
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This work was supported by the National Health and Medical Research Council of Australia (NHMRC grant #566815 to E.L.F. and #350224, and #299974 to J.W-B. & E.L.F.). J.W-B. is an NHMRC Senior Research Fellow B. JAP is a CJ Martin Fellow of the NH&MRC.