The renin–angiotensin system in retinal health and disease: Its influence on neurons, glia and the vasculature

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Abstract

Renin–Angiotensin System is classically recognized for its role in the control of systemic blood pressure. However, the retina is recognized to have all the components necessary for angiotensin II formation, suggestive of a role for Angiotensin II in the retina that is independent of the systemic circulation. The most well described effects of Angiotensin II are on the retinal vasculature, with roles in vasoconstriction and angiogenesis. However, it is now emerging that Angiotensin II has roles in modulation of retinal function, possibly in regulating GABAergic amacrine cells. In addition, Angiotensin II is likely to have effects on glia. Angiotensin II has also been implicated in retinal vascular diseases such as Retinopathy of Prematurity and diabetic retinopathty, and more recently actions in choroidal neovascularizaiton and glaucoma have also emerged. The mechanisms by which Angiotensin II promotes angiogensis in retinal vascular diseases is indicative of the complexity of the RAS and the variety of cell types that it effects. Indeed, these diseases are not purely characterized by direct effects of Angiotensin II on the vasculature. In retinopathy of prematurity, for example, blockade of AT1 receptors prevents pathological angiogenesis, but also promotes revascularization of avascular regions of the retina. The primary site of action of Angiotensin II in this disease may be on retinal glia, rather than the vasculature. Indeed, blockade of AT1 receptors prevents glial loss and promotes the re-establishment of normal vessel growth. Blockade of RAS as a treatment for preventing the incidence and progression of diabetic retinopathy has also emerged based on a series of studies in animal models showing that blockade of the RAS prevents the development of a variety of vascular and neuronal deficits in this disease. Importantly these effects may be independent of actions on systemic blood pressure. This has culminated recently with the completion of several large multi-centre clinical trials that showed that blockade of the RAS may be of benefit in some at risk patients with diabetes. With the emergence of novel compounds targeting different aspects of the RAS even more effective ways of blocking the RAS may be possible in the future.

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.

References (326)

  • P. Chen et al.

    Role of angiotensin II in retinal leukostasis in the diabetic rat

    Exp. Eye Res.

    (2006)
  • H. Choi et al.

    Mechanism of angiotensin II-induced superoxide production in cells reconstituted with angiotensin type 1 receptor and the components of NADPH oxidase

    J. Biol. Chem.

    (2008)
  • C.C. Chua et al.

    Upregulation of vascular endothelial growth factor by angiotensin II in rat heart endothelial cells

    Biochim. Biophys. Acta

    (1998)
  • O. Chung et al.

    Physiological and pharmacological implications of AT1 versus AT2 receptors

    Kidney Int.

    (1998)
  • W.H. Constad et al.

    Use of an angiotensin converting enzyme inhibitor in ocular hypertension and primary open-angle glaucoma

    Am. J. Ophthalmol.

    (1988)
  • V.I. Cook et al.

    The AT2 angiotensin receptor subtype predominates in the 18 day gestation fetal rat brain

    Brain Res.

    (1991)
  • C. Costagliola et al.

    Effect of oral losartan potassium administration on intraocular pressure in normotensive and glaucomatous human subjects

    Exp. Eye Res.

    (2000)
  • K.H. Datum et al.

    Angiotensin-like immunoreactive cells in the chicken retina

    Exp. Eye Res.

    (1991)
  • C.F. Deschepper et al.

    Colocalization of angiotensinogen and glial fibrillary acidic protein in astrocytes in rat brain

    Brain Res.

    (1986)
  • F. Dijk et al.

    An immunocytochemical study on specific amacrine cell subpopulations in the rat retina after ischemia

    Brain Res.

    (2004)
  • C.J. Dong et al.

    GABAc feedback pathway modulates the amplitude and kinetics of ERG b-wave in a mammalian retina in vivo

    Vision Res.

    (2002)
  • M.I. Dorrell et al.

    Mechanisms of endothelial cell guidance and vascular patterning in the developing mouse retina

    Prog. Retin. Eye Res.

    (2006)
  • L.E. Downie et al.

    Neuronal and glial cell expression of angiotensin II type 1 (AT1) and type 2 (AT2) receptors in the rat retina

    Neuroscience

    (2009)
  • G.J. Downing et al.

    First-trimester villous placenta has high prorenin and active renin concentrations

    Am. J. Obstet. Gynecol.

    (1995)
  • C.B. Duarte et al.

    Glutamate in life and death of retinal amacrine cells

    Gen. Pharmacol.

    (1998)
  • A.B. Fulton et al.

    The neurovascular retina in retinopathy of prematurity

    Prog. Retin. Eye Res.

    (2009)
  • H. Funatsu et al.

    Relation of diabetic macular edema to cytokines and posterior vitreous detachment

    Am. J. Ophthalmol.

    (2003)
  • R.F. Gariano

    Cellular mechanisms in retinal vascular development

    Prog. Retin. Eye Res.

    (2003)
  • N.J. Abbott et al.

    Astrocyte–endothelial interactions at the blood-brain barrier

    Nat. Rev. Neurosci.

    (2006)
  • M. Abdouh et al.

    Early upregulation of kinin B1 receptors in retinal microvessels of the streptozotocin-diabetic rat

    Br. J. Pharmacol.

    (2003)
  • A.Y. Abramov et al.

    Expression and modulation of an NADPH oxidase in mammalian astrocytes

    J. Neurosci.

    (2005)
  • L.P. Aiello et al.

    Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders

    N. Engl. J. Med.

    (1994)
  • L.P. Aiello et al.

    Diabetic retinopathy

    Diabetes Care

    (1998)
  • Y. Aizu et al.

    Degeneration of retinal neuronal processes and pigment epithelium in the early stage of the streptozotocin-diabetic rats

    Neuropathology

    (2002)
  • J.D. Akula et al.

    Rod photoreceptor function predicts blood vessel abnormality in retinopathy of prematurity

    Invest. Ophthalmol. Vis. Sci.

    (2007)
  • O. Alcazar et al.

    (Pro)renin receptor is expressed in human retinal pigment epithelium and participates in extracellular matrix remodeling

    Exp. Eye Res.

    (2009)
  • D. Alcorn et al.

    Angiotensin receptors and development: the kidney

    Clin. Exp. Pharmacol. Physiol.

    (1996)
  • T. Amemiya

    Dark adaptation in diabetics

    Ophthalmologica

    (1977)
  • A. Ames et al.

    Energy metabolism of rabbit retina as related to function: high cost of Na+ transport

    J. Neurosci.

    (1992)
  • A. Amsterdam et al.

    Identification of 315 genes essential for early zebrafish development

    Proc. Natl. Acad. Sci. U. S. A.

    (2004)
  • A.J. Barber et al.

    Neural apoptosis in the retina during experimental and human diabetes. Early onset and effect of insulin

    J. Clin. Invest.

    (1998)
  • A.M. Barnaby et al.

    Development of scotopic visual thresholds in retinopathy of prematurity

    Invest. Ophthalmol. Vis. Sci.

    (2007)
  • M.A. Bearse et al.

    Local multifocal oscillatory potential abnormalities in diabetes and early diabetic retinopathy

    Invest. Ophthalmol. Vis. Sci.

    (2004)
  • K. Bedard et al.

    The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology

    Physiol. Rev.

    (2007)
  • J.L. Berka et al.

    Renin-containing Muller cells of the retina display endocrine features

    Invest. Ophthalmol. Vis. Sci.

    (1995)
  • J.L. Berka et al.

    Renin-containing Muller cells of the retina display endocrine features

    Invest. Ophthalmol. Vis. Sci.

    (1995)
  • G.H. Bresnick et al.

    Oscillatory potential amplitudes. Relation to severity of diabetic retinopathy

    Arch. Ophthalmol.

    (1987)
  • G.H. Bresnick et al.

    Predicting progression to severe proliferative diabetic retinopathy

    Arch. Ophthalmol.

    (1987)
  • B.V. Bui et al.

    ACE inhibition salvages the visual loss caused by diabetes

    Diabetologia

    (2003)
  • B.V. Bui et al.

    Altered retinal function and structure after chronic placental insufficiency

    Invest. Ophthalmol. Vis. Sci.

    (2002)
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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.

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