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This review offers a contemporary history of the renin-angiotensin (RAS) and kallikrein-kinin (KKS) systems with emphasis on how these complex systems affect the eye. It describes the types of communication (cross-talk) between the two systems and evaluates their potential role in the development of diabetic retinopathy, diabetic macular edema, age-related macular degeneration, glaucoma, and uveitis. In addition to detailing the important physiological actions of components of the RAS and KKS, possibilities are suggested for new therapeutic avenues in the treatment of common ocular diseases. Historical notes indicate the major events in this research area, marking four decades from the first publication on the discovery of renin and angiotensin converting enzyme in the eye to the present time. [ABSTRACT FROM AUTHOR]

Retinal arterial macroaneurysms are characterized by the acquired fusiform or saccular dilatations of the retinal artery. Angiotensin II (Ang II) is a major signal molecule of the renin–angiotensin system, which exerts a range of pathogenic actions that are relevant to retinal vascular abnormalities. We aimed to study the effect of Ang II on retinal vessels and explore its relationship with retinal aneurysmal disease. C57BL/6J male mice were administered Ang II at 1000 ng/kg/min for 28 days, and the mice given saline served as controls. The mice in the treatment group were treated once daily by gastric gavage of candesartan cilexetil (an antagonist of Ang II type 1 (AT1) receptor) at 100 mg/kg/day. The in vivo imaging of murine retinas was performed using fundus photography, optical coherence tomography, fluorescein angiography, and indocyanine green angiography at 7th, 14th, and 28th days of infusion. At the end of the infusion and treatment, the morphological changes were evaluated by histopathological examination and electron microscopy; the levels of related proteins in murine retinas were examined by antibody array and Western blot analyses. We found that Ang II infusion induced aneurysm formation in mice retina, which presented as either solitary aneurysms or retinal arterial beading. The aneurysm formation was often accompanied with vessel leakage. Moreover, Ang II infusion itself may result in increased vascular permeability and ganglion cell and inner plexiform layer thickening. The blockade of AT1 receptors by systemic administration of candesartan cilexetil alleviated the Ang II-induced retinal vasculopathy. The protein level analysis further showed that Ang II upregulated IL-1β, PDGFR-β, and MMP-9 expression, and the expression of IL-1β could be inhibited by AT1 receptor antagonist. Our study provides evidence that Ang II is a crucial factor in retinal aneurysm formation and vessel leakage. It is probably the combined effect of Ang II on vessel inflammatory response, pericyte function, and extracellular matrix remodeling that predisposes the retinal arterial wall to aneurysm formation and blood-retinal barrier breakdown. • Angiotensin II is a crucial factor in retinal aneurysm formation and vessel leakage. • Angiotensin II upregulated IL-1β, PDGFR-β, and MMP-9 expression in murine retina. • The effect of angiotensin Ⅱ on vessel inflammation and ECM remodeling predisposed the retinal arterial wall to aneurysm formation and BRB breakdown. [ABSTRACT FROM AUTHOR]

Abstract: The effect of topical application of SPP 635, a renin inhibitor, on intraocular pressure (IOP) was evaluated in the eyes of monkeys with laser induced unilateral glaucoma. A multiple-dose study was performed in 8 glaucomatous monkey eyes with 3 concentrations of SPP 635, 0.2%, 0.3% and 0.4%. IOP was measured hourly for 6 h on each day of the study beginning at 9:30 a.m. Following one baseline day (untreated) and one vehicle-treated day (50 μl drop of vehicle to the glaucomatous eye at 9:30 a.m.), a 50 μl drop (25 μl × 2) of SPP 635, 0.2%, 0.3% or 0.4%, was topically applied to the glaucomatous eye at 9:30 a.m. and 3:30 p.m. for 5 consecutive days. Twice daily administration of each of the 3 concentrations of SPP 635 for 5 days significantly (p < 0.05) reduced IOP. The maximum reduction in IOP occurred 3 or 4 h after morning dosing and was 4.3 ± 0.8 (mean ± SEM) mmHg (14%) for 0.2% SPP 635, 5.3 ± 1.0 mmHg, (19%) for 0.3% SPP 635, and 8.0 ± 1.3 mmHg (25%) for 0.4% SPP 635. The longest duration of IOP reduction was for 6 h with 0.2% or 0.3% SPP 635, and was for at least 18 h with 0.4% concentration. Compared to 0.2% or 0.3% concentrations, 0.4% SPP 635 produced a greater (p < 0.05) and longer duration of IOP reduction (18 vs. 6 h). Mild conjunctival discharge appeared in 2 of 8 eyes, and hyperemia appeared in 2 eyes with the 0.3% and 0.4% concentrations on treatment days 3 and 5. Topically applied SPP 635, a new renin inhibitor, reduces IOP in glaucomatous monkeys in a dose-dependent manner. Renin inhibitors, are a novel class of compounds which may have potential for the treatment of glaucoma. [Copyright &y& Elsevier]

Abstract: Asymmetric dimethylarginine (ADMA), an endogenous competitive inhibitor of nitric oxide synthase, is generated in presence of type 1 protein arginine N-methyltransferase (PRMT-1) and is metabolized by dimethylarginine dimethylaminohydrolases (DDAHs). Reportedly ADMA is associated with endothelial dysfunction. The aim of this study is to investigate whether PRMT-1- and DDAHs-induced ADMA increase in diabetic rat retina and high glucose-treated bovine retinal capillary endothelial cells (BRCECs) is involved in reactive oxygen species (ROS)- and renin–angiotensin system (RAS)-mediated diabetic retinopathy. Rats were divided into four groups: sham-injected group, streptozotocin (STZ)-induced diabetic model group, STZ-induced diabetic model plus 12-week ACEI benazepril treatment group, and STZ-induced diabetic model plus 12-week ARB telmisartan treatment group. BRCECs were exposed to 5mM glucose, 30mM glucose, and 30mM glucose plus benazepril, telmisartan, diphenyliodonium (NADPH oxidase inhibitor, DPI), or N-Acetyl-l-cysteine (antioxidant and free radical scavenger, NAC) until passage four. We found that the concentrations of ADMA were significantly elevated in the plasma of diabetic rat models, and were significantly reduced by benazepril or telmisartan. DDAHs expression was decreased and PRMT-1 expression was increased in diabetic rat retina, which was reversed by benazepril. Telmisartan decreased PRMT-1 expression and increased DDAH II expression, but had no effect on DDAH I expression. In vitro, BRCECs exposed to high glucose had elevated ROS production, decreased cGMP, increased PRMT-1 expression, and decreased DDAH activity and DDAH II expression. Coincubating BRCECs with benazepril, telmisartan, DPI or NAC reversed the effects of high glucose. It can be concluded that PRMT-I and DDAHs-induced upregulation of ADMA levels might be involved in ROS- and RAS-mediated diabetic retinopathy. [Copyright &y& Elsevier]

Abstract: To study if the endogenous renin–angiotensin system affects diabetic retinal leukostasis, rats with streptozotocin-induced diabetes were treated with an ACE inhibitor (ramipril), an angiotensin II AT1 receptor antagonist (losartan) and the Ca channel blocker, (nifedipine). In the diabetic rats, these drug treatments reduced systolic blood pressure by ∼16mmHg but did not change blood glucose. After 2weeks, the rats were examined for retinal leukostasis in vivo with a scanning laser ophthalmoscope (SLO). Retinal leukostasis, which was defined as no movement of arrested leukocytes over 2min, was markedly higher in diabetic rats than normal controls (P <0.01). Leukostasis was significantly decreased by ramipril and losartan (P <0.01 vs. untreated diabetic rats) but was still higher than normal. Retinal leukostasis after nifedipine treatment was not significantly different than in untreated diabetic rats. The same trend was observed when leukostasis was analyzed on retinal flat mounts with concanavalin A and CD45 immunofluorescence; ramipril and losartan treatment, however, decreased leukostasis to values no different than controls. Retinal leukostasis was lowered by nifedipine (P <0.05, untreated diabetes vs. nifedipine-treated) but was still higher than in normal, ramipril-, or losartan-treated rats. Assays of gene expression of retinal intercellular adhesion molecule (ICAM-1) by semi-quantitative RT–PCR indicated that ICAM-1 mRNA was increased in diabetic rats but was decreased markedly by treatment with losartan or ramipril, and modestly by nifedipine. In summary, suppressing the activity of the endogenous renin–angiotensin system markedly decreases, perhaps even normalizes, the retinal leukostasis that accompanies type I diabetes in rats. These effects seem to be partly independent of blood pressure and to be associated with a decrease in ICAM-1 gene expression. Angiotensin II may, thus, mediate retinal leukostasis in early diabetes. [Copyright &y& Elsevier]

Abstract: To evaluate the effect of CS-088, an angiotensin AT1 receptor antagonist, on intraocular pressure (IOP) in monkey eyes with unilateral laser-induced glaucoma. A multiple-dose study was performed in 8 glaucomatous monkey eyes. One 50µl drop of CS-088, 2% or 4%, was topically applied to the glaucomatous eye at 9:30 a.m. and 3:30 p.m. for 5 consecutive days. IOP was measured hourly for 6 hours beginning at 9:30 a.m. for one baseline day, one vehicle-treated day, and daily for 5 days of treatment with CS-088. The washout period between the two drug concentrations was at least 2 weeks. Twice daily administration of 2 % CS-088 for 5 days did not reduce the IOP until the third dose on day 2 of the treatment regimen. A significant (p&#60;0.02) reduction in IOP began 1 hour after the third dose, and lasted for 3 hours. The maximum reduction in IOP was 5.3± 0.8 (mean±SEM) mmHg (15%) (p&#60;0.001), with the longest duration of IOP reduction of at least 6 hours after dosing on day 5. The 4% dose of CS-088 reduced (p&#60;0.05) IOP from 1 to 5 hours after the first dose. The maximum reduction in IOP was 6.9±1.0 mmHg (20%), with the longest duration of IOP reduction of at least 18 hours after administration on day 5. Both 2% and 4% CS-088 showed enhancement of the ocular hypotensive effect with repeated dosing. 4% CS-088 produced greater (p&#60;0.05) IOP reduction with longer duration of action than 2%. Topically applied CS-088, a new antagonist drug at the angiotensin AT1 receptor, reduced IOP in glaucomatous monkey eyes in a dose-dependent manner. [Copyright &y& Elsevier]

In 1889 Tigerstedt and Bergman identified the pressor effects of renal extracts, and termed the substance renin ([13]). 189, 2019, 107828 7 K.M. Mirabito Colafella, D.M. Bovee, A.H.J. Danser, The renin-angiotensin-aldosterone system and its therapeutic targets. 187, 2019, 107770 15 J.L. Wilkinson-Berka, V. Suphapimol, J.R. Jerome, D. Deliyanti, M.J. Allingham, Angiotensin II and aldosterone in retinal vasculopathy and inflammation. [Extracted from the article]

Microglial cells are important contributors to the neuroinflammation and blood vessel damage that occurs in ischemic retinopathies. We hypothesized that key effectors of the renin-angiotensin aldosterone system, angiotensin II (Ang II) and aldosterone, increase the density of microglia in the retina and stimulate their production of reactive oxygen species (ROS) as well as pro-angiogenic and pro-inflammatory factors. Two animal models were studied that featured up-regulation of Ang II or aldosterone and included transgenic Ren-2 rats which overexpress renin and Ang II in tissues including the retina, and Sprague Dawley rats with ischemic retinopathy and infused with aldosterone. Complementary studies were performed in primary cultures of retinal microglia from neonatal Sprague Dawley rats exposed to hypoxia (0.5% O 2) and inhibitors of the angiotensin type 1 receptor (valsartan), the mineralocorticoid receptor (spironolactone) or aldosterone synthase (FAD286). In both in vivo models, the density of ionized calcium-binding adaptor protein-1 labelled microglia/macrophages was increased in retina compared to genetic or vehicle controls. In primary cultures of retinal microglia, hypoxia increased ROS (superoxide) levels as well as the expression of the NADPH oxidase (NOX) isoforms, NOX1, NOX2 and NOX4. The elevated levels of ROS as well as NOX2 and NOX4 were reduced by all of the treatments, and valsartan and FAD286 also reduced NOX1 mRNA levels. A protein cytokine array of retinal microglia revealed that valsartan, spironolactone and FAD286 reduced the hypoxia-induced increase in the potent pro-angiogenic and pro-inflammatory agent, vascular endothelial growth factor as well as the inflammatory factors, CCL5 and interferon γ. Valsartan also reduced the hypoxia-induced increase in IL-6 and TIMP-1 as well as the chemoattractants, CXCL2, CXCL3, CXCL5 and CXCL10. Spironolactone and FAD286 reduced the levels of CXCL2 and CXCL10, respectively. In conclusion, our findings that both Ang II and aldosterone influence the activation of retinal microglia implicates the renin-angiotensin aldosterone system in the pathogenesis of ischemic retinopathies. • Angiotensin II and aldosterone increased the density of microglia in the retina. •Blockade of the angiotensin type 1 receptor and aldosterone reduced reactive oxygen species and the expression of NADPH oxidase (NOX) isoforms in retinal microglia exposed to hypoxia. •Blockade of the angiotensin type 1 receptor and aldosterone reduced the protein levels of pro-angiogenic and pro-inflammatory factors produced by retinal microglia in response to hypoxia. [ABSTRACT FROM AUTHOR]

Several lines of evidence support the existence of a renin-angiotensin system (RAS) in the retina that is separated from the blood stream by the retinal pigment epithelium (RPE). Under physiological conditions, increased activity of intraretinal RAS regulates neuronal activity of the retina but patho-physiologically participates in retinal degeneration such as hypertensive or diabetic retinopathy. Interestingly, the RPE appears to be a modulator of intraretinal RAS in response to changes in systemic RAS. As increased systemic RAS activity is associated with increased sympathetic tonus, we investigated whether systemic β-adrenergic stimulation of the RPE also modulates renin expression in the RPE. In vivo , the mouse RPE expresses the β-adrenergic receptor subtypes 1 and 2. Staining of retina sagittal sections showed tyrosine hydroxylase positive nerve endings in the choroid indicating adrenaline/noradrenaline production sites in close proximity to the RPE. Systemic infusion of isoproterenol increased renin expression in the RPE but not in the retina. This increase was sensitive to concomitant systemic application of the angiotensin-2 receptor-type-1 blocker losartan. In vitro analysis of renin gene expression using polarized porcine RPE showed that the activity of the renin promoter can be increased by cAMP stimulation (IBMX/forskolin) but was not influenced by angiotensin-2. Thus, with the identification of the β-adrenergic system we added a new regulator of the retinal RAS with relevance for retinal function and pathology. Furthermore, it appears that the RPE is not only a close interaction partner of the photoreceptors but also a regulator or retinal activity in general. • The retinal pigment epithelium (RPE) forms an interface between the body system and retina. • Basolateral plasma membrane receptors make the RPE being an active interface between the body system and the retina. • We show that β-adrenergic stimulation increases the renin production by the RPE and thus retinal renin-angiotensin system. • Close sympathetic nerves in the choroid suggest that sympathetic activity influences retinal function and retinal pathology. [ABSTRACT FROM AUTHOR]

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]

Angiotensin II and aldosterone are the main effectors of the renin-angiotensin aldosterone system (RAAS) and have a central role in hypertension as well as cardiovascular and renal disease. The localization of RAAS components within the retina has led to studies investigating the roles of angiotensin II, aldosterone and the counter regulatory arm of the pathway in vision-threatening retinopathies. This review will provide a brief overview of RAAS components as well as the vascular pathology that develops in the retinal diseases, retinopathy of prematurity, diabetic retinopathy and neovascular age-related macular degeneration. The review will discuss pre-clinical and clinical evidence that modulation of the RAAS alters the development of vasculopathy and inflammation in the aforementioned retinopathies, as well as the emerging role of aldosterone and the mineralocorticoid receptor in central serous chorioretinopathy. • A local renin-angiotensin aldosterone system exists within the retina. • Angiotensin II and aldosterone promote vascular pathology and inflammation in the retina. • Blockade of renin, the AT1R and ACE reduce retinal vasculopathy and inflammation. • Blockade of aldosterone/MRreduce retinal edema and vasculopathy. [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]

The renin-angiotensin-aldosterone system (RAAS) plays a pivotal role in the regulation of blood pressure and body fluid homeostasis and is a mainstay for the treatment of cardiovascular and renal diseases. Angiotensin II and aldosterone are the two most powerful biologically active products of the RAAS, inducing all of the classical actions of the RAAS including vasoconstriction, sodium retention, tissue remodeling and pro-inflammatory and pro-fibrotic effects. In recent years, new components of the RAAS have been discovered beyond the classical pathway that have led to the identification of depressor or so-called protective RAAS pathways and the development of novel therapies targeting this system. Moreover, dual inhibitors which block the RAAS and other systems involved in the regulation of blood pressure or targeting upstream of angiotensin II by selectively deleting liver-derived angiotensinogen, the precursor to all angiotensins, may provide superior treatment for cardiovascular and renal diseases and revolutionize RAAS-targeting therapy. • RAAS plays key roles in cardio-metabolic health and disease. • Classical inhibitors block angiotensin I and II generation or downstream effects. • Latest form of RAAS inhibitor is combination of an ARB with NEP inhibitor (ARNI). • RAAS agonists target the depressor or so called protective RAAS pathways. • Deletion of liver-derived angiotensinogen may revolutionize RAAS inhibition. [ABSTRACT FROM AUTHOR]