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

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.