angiotensin-i and Diabetic-Retinopathy

Diabetic retinopathy develops in patients with both type 1 and type 2 diabetes and is the major cause of vision loss and blindness in the working population. In diabetes, damage to the retina occurs in the vasculature, neurons and glia resulting in pathological angiogenesis, vascular leakage and a loss in retinal function. The renin-angiotensin system is a causative factor in diabetic microvascular complications inducing a variety of tissue responses including vasoconstriction, inflammation, oxidative stress, cell hypertrophy and proliferation, angiogenesis and fibrosis. All components of the renin-angiotensin system including the angiotensin type 1 and angiotensin type 2 receptors have been identified in the retina of humans and rodents. There is evidence from both clinical and experimental models of diabetic retinopathy and hypoxic-induced retinal angiogenesis that the renin-angiotensin system is up-regulated. In these situations, retinal dysfunction has been linked to angiotensin-mediated induction of growth factors including vascular endothelial growth factor, platelet-derived growth factor and connective tissue growth factor. Evidence to date indicates that blockade of the renin-angiotensin system can confer retinoprotection in experimental models of diabetic retinopathy and ischemic retinopathy. This review examines the role of the renin-angiotensin system in diabetic retinopathy and the potential of its blockade as a treatment strategy for this vision-threatening disease.

Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme 2; Animals; Animals, Genetically Modified; Diabetic Retinopathy; Humans; Hypertension; Neovascularization, Pathologic; Peptide Fragments; Peptidyl-Dipeptidase A; Renin; Renin-Angiotensin System; Retina

O-GlcNAcylation of cellular proteins contributes to the pathophysiology of diabetes and evidence supports a role for augmented O-GlcNAcylation in diabetic retinopathy. The aim of this study was to investigate the impact of the renin-angiotensin system on retinal protein O-GlcNAcylation.. Mice fed a high-fat diet were treated chronically with the angiotensin-converting enzyme inhibitor captopril or captopril plus the angiotensin-(1-7) Mas receptor antagonist A779. Western blotting and quantitative polymerase chain reaction were used to analyze retinal homogenates. Similar analyses were performed on lysates from human MIO-M1 retinal Müller cell cultures exposed to media supplemented with angiotensin-(1-7). Culture conditions were manipulated to influence the hexosamine biosynthetic pathway and/or signaling downstream of the Mas receptor.. In the retina of mice fed a high-fat diet, captopril attenuated protein O-GlcNAcylation in a manner dependent on Mas receptor activation. In MIO-M1 cells, angiotensin-(1-7) or adenylate cyclase activation were sufficient to enhance cyclic AMP (cAMP) levels and inhibit O-GlcNAcylation. The repressive effect of cAMP on O-GlcNAcylation was dependent on exchange protein activated by cAMP (EPAC), but not protein kinase A, and was recapitulated by a constitutively active variant of the small GTPase Rap1. We provide evidence that cAMP and angiotensin-(1-7) act to suppress O-GlcNAcylation by inhibition of O-GlcNAc transferase (OGT) activity. In cells exposed to an O-GlcNAcase inhibitor or hyperglycemic culture conditions, mitochondrial superoxide levels were elevated; however, angiotensin-(1-7) signaling prevented the effect.. Angiotensin-(1-7) inhibits retinal protein O-GlcNAcylation via an EPAC/Rap1/OGT signaling axis.

Topics: Angiotensin I; Animals; Captopril; Cyclic AMP-Dependent Protein Kinases; Diabetic Retinopathy; Mice; N-Acetylglucosaminyltransferases; Peptide Fragments; Renin-Angiotensin System; Retina; Signal Transduction

Despite evidence that hyperactivity of the vasodeleterious axis (ACE/angiotensin II (Ang II)/AT1 receptor) of the renin-angiotensin system (RAS) is associated with the pathogenesis of diabetic retinopathy (DR) use of the inhibitors of this axis has met with limited success in the control of this pathophysiology. We investigated the hypothesis that enhancing the local activity of the recently established protective axis of the RAS, ACE2/Ang-(1-7), using adeno-associated virus (AAV)-mediated gene delivery of ACE2 or Ang-(1-7) would confer protection against diabetes-induced retinopathy. Genes expressing ACE2 and Ang-(1-7) were cloned in AAV vector. The effects of ocular AAV-ACE2/Ang-(1-7) gene transfer on DR in diabetic eNOS(-/-) mice and Sprague-Dawley (SD) rats were examined. Diabetes was associated with approximately tenfold and greater than threefold increases in the ratios of ACE/ACE2 and AT1R/Mas mRNA levels in the retina respectively. Intraocular administration of AAV-ACE2/Ang-(1-7) resulted in significant reduction in diabetes-induced retinal vascular leakage, acellular capillaries, infiltrating inflammatory cells and oxidative damage in both diabetic mice and rats. Our results demonstrate that DR is associated with impaired balance of retinal RAS. Increased expression of ACE2/Ang-(1-7) overcomes this imbalance and confers protection against DR. Thus, strategies enhancing the protective ACE2/Ang-(1-7) axis of RAS in the eye could serve as a novel therapeutic target for DR.

Topics: Angiotensin I; Angiotensin-Converting Enzyme 2; Animals; Dependovirus; Diabetic Retinopathy; Disease Models, Animal; Enzyme Activation; Gene Expression; Gene Order; Genetic Therapy; Genetic Vectors; Intravitreal Injections; Male; Mice; Mice, Knockout; Nitric Oxide Synthase Type III; Oxidative Stress; Peptide Fragments; Peptidyl-Dipeptidase A; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System; Retina; Retinal Vessels

To investigate whether diabetic retinopathy (DR) is associated with abnormalities in: (i) aqueous humour Angiotensin I (Ang I) and Angiotensin II (Ang II) levels; and (ii) plasma Ang I, soluble P-selectin, lipoprotein (a) (Lp(a)), endothelial markers and haemorheological abnormalities.. Cross-sectional study of diabetic patients and healthy controls undergoing cataract surgery.. 21 diabetic patients (12 males; mean age 67.0 years) were studied. Plasma levels of Ang II were lower in diabetics compared with controls (p<0.05). There were no differences in mean aqueous Ang I and Ang II levels in diabetics with or without proliferative DR compared with controls. Mean systolic blood pressure was higher in Group 1 patients (p=0.02). Patients with DR also demonstrated high Lp (a) and abnormal haemorheological factors (fibrinogen, white cell count).. Ang I and Ang II do not significantly contribute to the pathogenesis of DR. Patients with DR also had abnormal Lp (a) and haemorheological factors. The role of hypertension in the pathogenesis of DR needs further evaluation.

Topics: Aged; Angiotensin I; Angiotensin II; Aqueous Humor; Blood Pressure; Cell Division; Cross-Sectional Studies; Diabetic Retinopathy; Endothelium, Vascular; Female; Hemorheology; Humans; Lipoprotein(a); Male; Neovascularization, Pathologic; P-Selectin; Retinal Neovascularization; Retinal Vessels; Thrombosis

Ocular tissues contain renin and ocular fluids contain prorenin in amounts that are too high to be explained by admixture with blood or diffusion from blood. It was the purpose of the present study to obtain further evidence for the presence of a local renin-angiotensin system (RAS) in the eye.. The authors measured the concentrations of angiotensins I and II (ANG I and II) in vitreous fluid and ocular tissues of anesthetized pigs and in human aqueous, vitreous, and subretinal fluid obtained during eye surgery.. In tissues obtained from normal porcine eyes (anterior uveal tract, neural retina, retinal pigment epithelium + choroid), ANG I and II were 5- to 100-fold higher than could be accounted for by contamination with blood. ANG I and II in ocular tissues are therefore unlikely to be derived from the circulation. In porcine vitreous fluid, ANG I and II were close to the limit of detection. In addition, during a 2-hour infusion of 125I-ANG I in the rabbit, 125I-ANG I in vitreous fluid reached a level only 1% of the level in arterial plasma. Thus, in the presence of an intact blood-retinal barrier, little or no ANG I or II enters the vitreous compartment. In human ocular fluids obtained from diseased eyes, ANG I and II levels were readily measurable and correlated linearly with the level of serum albumin, indicating that after partial breakdown of the BRB, diffusion of ANG I and II from the circulation into the eye may occur.. Results indicate that both ANG I and II are generated locally in ocular tissues with little leakage into ocular fluids. These findings, together with previously published data on renin and prorenin, show a high degree of compartmentalization of the RAS in the eye and are in agreement with similar findings in other tissues, where there is evidence for the existence of a local RAS.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Angiotensin I; Angiotensin II; Animals; Blood-Retinal Barrier; Child; Chromatography, High Pressure Liquid; Diabetic Retinopathy; Eye; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Peptidyl-Dipeptidase A; Rabbits; Renin-Angiotensin System; Swine