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As many other organs, the retina has a local renin-angiotensin-system (RAS). All main elements of the RAS are active in the retina: renin, angiotensinogen, angiotensin-converting enzymes. The functional role of the intraretinal RAS is not fully understood. So far, histological and functional analysis point to a regulation of ganglion cell activity and maybe also of bipolar cell activity, but it is not clear how RAS contributes to retinal signal processing. In contrast to local RAS in other organs, the retinal RAS is clearly separated from the systemic RAS. The angiotensin-2 (AngII)/AngI ratio in the retina is different to that in the plasma. However, it appears that the retinal pigment epithelium (RPE), that forms the outer blood/retina barrier, is a major regulator of the retinal RAS by producing renin. Interestingly, comparable to the kidney, the renin production in the RPE is under control of the angiotensin-2 receptor type-1 (AT1). AT1 localizes to the basolateral membrane of the RPE and faces the blood side of the blood/retina barrier. Increases in systemic AngII reduce renin production in the RPE and therefore decrease the intraretinal RAS activity. The relevance of the local RAS for retinal function remains unclear. Nevertheless, it is of fundamental significance to understand the pathology of systemically induced retinal diseases such as hypertension or diabetes. • The retinal renin-angiotensin system (RAS) plays a role in neuronal processing and systemic induced retinal degenerations. • As the retinal pigment epithelium (RPE) expresses renin it is one of the major regulators of the retinal RAS. • The regulation of renin expression in the RPE is under influence from changes in systemic RAS or by adrenergic impact. • Thus, the RPE functions as interface between the body system and retinal function by modulation of retinal RAS activity. [ABSTRACT FROM AUTHOR]

The renin-angiotensin system (RAS) plays a vital role in cardiovascular physiology and body homeostasis. In addition to circulating RAS, a local RAS exists in the retina. Dysfunction of local RAS, resulting in increased levels of Angiotensin II (Ang II) and activation of AT1R-mediated signaling pathways, contributes to tissue pathophysiology and end-organ damage. Activation of AT2R on other hand is known to counteract the effects of AT1R activation and produce anti-inflammatory and anti-oxidative effects. We examined the expression of angiotensin receptors in the retina by using transgenic dual reporter mice and by real-time RT-PCR. We further evaluated the effects of C21, a selective agonist of AT2R, in reducing Ang II, lipopolysaccharide (LPS) and hydrogen peroxide induced oxidative stress and inflammatory responses in cultured human ARPE-19 cells. We showed that both AT1Ra and AT2R positive cells are detected in different cell types of the eye, including the RPE/choroid complex, ciliary body/iris, and neural retina. AT1Ra is more abundantly expressed than AT2R in mouse retina, consistent with previous reports. In the neural retina, AT1Ra are also detected in photoreceptors whereas AT2R are mostly expressed in the inner retinal neurons and RGCs. In cultured human RPE cells, activation of AT2R with C21 significantly blocked Ang II, LPS and hydrogen peroxide -induced NF-κB activation and inflammatory cytokine expression; Ang II and hydrogen peroxide-induced reactive oxygen species (ROS) production and MG132-induced apoptosis, comparable to the effects of Angiotensin-(1–7) (Ang-(1–7)), another protective component of the RAS, although C21 is more potent in reducing some of the effects induced by Ang II, whereas Ang-(1–7) is more effective in reducing some of the LPS and hydrogen peroxide-induced effects. These results suggest that activation of AT2R may represent a new therapeutic approach for retinal diseases. • A local renin angiotensin system (RAS) exists in the retina and plays a critical role in retinal neurovascular function. Dysfunction of local RAS contributes to tissue pathophysiology and end-organ damage. • By using a dual reporter mice, this original report showed that both AT1Ra and AT2R positive cells are detected in different cell types of the eye, including the RPE/choroid complex, ciliary body/iris, and neural retina. • In cultured human RPE cells, activation of AT2R with a selective agonist significantly blocked NF-kB activation, inflammatory cytokine expression; and reactive oxygen species (ROS) production, comparable to the effects of Ang-(1-7), another protective component of the RAS. • These results suggest that activation of AT2R may represent a new therapeutic approach for retinal diseases. [ABSTRACT FROM AUTHOR]

The retina is known to have a local renin-angiotensin system (RAS) and dysfunction in the RAS is often associated with diseases of the retinal vasculature that cause irreversible vision loss. Regulation of the retinal vasculature to meet the metabolic needs of the tissues occurs through a mechanism called neurovascular coupling, which is critical for maintaining homeostatic function and support for neurons. Neurovascular coupling is the process by which support cells, including glia, regulate blood vessel calibre and blood flow in response to neural activity. In retinal vascular diseases, this coupling mechanism is often disrupted. However, the role that angiotensin II (Ang II), the main effector peptide of the RAS, has in regulating both the retinal vasculature and neurovascular coupling is not fully understood. As components of the RAS are located on the principal neurons, glia and blood vessels of the retina, it is possible that Ang II has a role in regulating communication and function between these three cell types, and therefore the capacity to regulate neurovascular coupling. This review focuses on components of the RAS located on the retinal neurovascular unit, and the potential of this system to contribute to blood flow modulation in the healthy and compromised retina. • The retina has its own independent renin-angiotensin system. • Regulation of the vasculature by glia may involve the renin-angiotensin system. • Microglia are immune cells that may be involved in modulation of the renin-angiotensin system. • Retinal vascular diseases are associated with anomalies in renin-angiotensin signalling. [ABSTRACT FROM AUTHOR]