angiogenin and Diabetic-Retinopathy

Diabetic macular oedema (DMO), a leading cause of preventable visual loss in the working population, is caused by an increase in microvascular endothelial cell permeability, and its prevalence is on the increase in parallel with the rising worldwide prevalence of diabetes. It is known that retinal vascular leakage in DMO is contributed to by VEGF upregulation as well as non-VEGF dependent inflammatory pathways, and the potential use of anti-inflammatory agents such as the glucocorticoids, including dexamethasone are being extensively studied. However, the mechanisms of action of dexamethasone in DMO reduction are not fully understood. Using human primary retinal endothelial cells (REC) the in vitro effect of dexamethasone in modulating the proliferation, permeability and gene expression of key tight and adheren junction components, and the expression of angiopoietins (Ang) 1 and 2 in high (25 mM) glucose conditions were investigated. High glucose decreased REC proliferation, an effect that was reversed by dexamethasone. High glucose conditions significantly increased REC permeability and decreased claudin-5, occludin and JAM-A gene expression; dexamethasone was effective in partially reversing these changes, restoring EC permeability to the normal or near normal state. High glucose levels resulted in reduction of Ang1 secretion, although Ang2 levels were consistently high. DEX increased Ang1 and decreased Ang2, indicating that the balance of Ang1/Ang2 may be important in determining functional changes in REC under high glucose conditions.

Topics: Aged; Aged, 80 and over; Animals; Cell Adhesion Molecules; Cell Membrane Permeability; Cell Proliferation; Cells, Cultured; Claudin-5; Dexamethasone; Diabetic Retinopathy; Endothelial Cells; Enzyme-Linked Immunosorbent Assay; Female; Gene Expression Regulation; Glucocorticoids; Glucose; Humans; Macular Edema; Male; Middle Aged; Real-Time Polymerase Chain Reaction; Receptors, Cell Surface; Retina; Ribonuclease, Pancreatic; RNA; Sweetening Agents

Diabetic retinopathy (DR) develops in a significant proportion of patients with chronic diabetes, characterized by retinal macular edema and abnormal retinal vessel outgrowth leading to vision loss. Chrysin, a naturally-occurring flavonoid found in herb and honeycomb, has anti-inflammatory, antioxidant, and anti-cancer properties. This study sought to determine the protective effects of chrysin on retinal neovascularization with abnormal vessels and blood-retinal barrier (BRB) breakdown in 33 mM glucose-exposed human retinal endothelial cells and in db/db mouse eyes. High glucose caused retinal endothelial apoptotic injury, which was inhibited by submicromolar chrysin. This compound diminished the enhanced induction of HIF-1α, vascular endothelial growth factor (VEGF), and VEGF receptor-2 (VEGFR2) in high glucose-exposed retinal endothelial cells. Consistently, oral administration of 10 mg/kg chrysin reduced the induction of these proteins in db/db mouse eye tissues. In addition, chrysin restored the decrement of VE-cadherin and ZO-1 junction proteins and PECAM-1 in hyperglycemia-stimulated retinal endothelial cells and diabetic mouse retina, possibly maintaining tight cell-cell interactions of endothelial cells and pericytes. Anti-apoptotic chrysin reduced the up-regulation of Ang-1, Ang-2, and Tie-2 crucial to retinal capillary occlusion and BRB permeability. Furthermore, orally treating chrysin inhibited acellular capillary formation, neovascularization, and vascular leakage observed in diabetic retinas. These observations demonstrate, for the first time, that chrysin had a capability to encumber diabetes-associated retinal neovascularization with microvascular abnormalities and BRB breakdown.

Topics: Animals; Antigens, CD; Apoptosis; Cadherins; Diabetic Retinopathy; Flavonoids; Glucose; Humans; Hyperglycemia; Hypoxia-Inducible Factor 1, alpha Subunit; Male; Mice; Mice, Inbred C57BL; Platelet Endothelial Cell Adhesion Molecule-1; Receptor, TIE-2; Retinal Neovascularization; Ribonuclease, Pancreatic; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2; Zonula Occludens-1 Protein

Angiogenin levels are increased in children and adolescent patients with type 1 diabetes, regardless of the extent of diabetic microangiopathy. However, little is known about the angiogenin concentrations in adults with type 1 diabetes. Thus we studied its level in middle aged subjects with the presence of diabetic nephro-, retino and neuropathy.. We investigated the data of 57 (age 39±6.6 years, 45.6% of males) patients with type 1 diabetes and 38 age-matched control subjects without diabetes (age 37.1±5.9 years, 42.1% of males), including medical histories, evidences of microangiopathy and serum angiogenin concentrations.. Serum angiogenin level was lower in patients with type 1 diabetes [384.2(190.4-999.8) ng/ml] compared to controls [460.4(230.6-708.2) ng/ml], p=0.04. In patients with overt diabetic nephropathy the angiogenin level was higher when compared to patients without nephropathy [568.2(269.6-999.8) vs 369.4(190.4-999.8) ng/ml, p=0.01]. There were no differences between angiogenin levels in subgroups of patients distinguished by the presence of other microvascular complications or other concomitant vascular risk factors despite cigarette smoking [smokers: 516.2(294.4-999.8) vs. non-smokers: 372.1(190.4-924.8) ng/ml, p=0.01].. Regardless of the presence of diabetic microangiopathy, angiogenin level in middle-aged type 1 diabetes patients is lower than in controls. The presence of overt nephropathy and smoking habit in middle-aged patients with type 1 diabetes are associated with higher angiogenin level.

Topics: Adult; Case-Control Studies; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Female; Gene Expression Regulation; Glomerular Filtration Rate; Humans; Male; Neovascularization, Pathologic; Ribonuclease, Pancreatic

Diabetic retinopathy is the most common cause of vision loss in young adults in developed countries. The disease therapy with anti-vascular endothelial growth factor (VEGF) agents gives some positive results, but is associated with retinal ischemia and vasoconstriction. Therefore, determination of factors involved in the physiological and pathological angiogenesis in the diabetic eye is of great importance for understanding of the pathogenesis of diabetic retinopathy and its effective treatment. Previously, we found that diabetic patients were characterized by increased serum concentration of VEGF, but decreased levels of other proangiogenic factor-angiogenin. The involvement of VEGF in pathogenesis of diabetic retinopathy is well established, but there is lack of data regarding angiogenin in retinopathy. Therefore, in the present study we measured angiogenin concentration in vitreous and serum samples of the patients with type 1 diabetes to determine its role in diabetic retinopathy. In addition, in each time, we compared the level of angiogenin with level of VEGF as a known factor involved in the pathogenesis of the disease. Angiogenin was found to be significantly more abundant in serum than in vitreous in both diabetic groups. In addition, patients with retinopathy had twofold lower vitreous angiogenin levels than diabetic individuals without complications. On the contrary, vitreous concentration of VEGF was dramatically increased only in participants with retinopathy. Patients without diabetic complications had significantly lower VEGF levels in vitreous than in serum and were characterized by high local and systemic concentration of angiogenin. These data suggest a local imbalance between two proangiogenic factors-VEGF and angiogenin in retinopathy. Low vitreous concentration of angiogenin in diabetic patients suggests that this factor is not responsible for pathological neovascularization in diabetic eye. Further studies will elucidate if angiogenin can be used to improve the insufficient angiogenesis in diabetes and prevent retinal ischemia after retinopathy treatment with anti-VEGF agents.

Topics: Diabetes Mellitus, Type 1; Diabetic Retinopathy; Female; Humans; Male; Middle Aged; Ribonuclease, Pancreatic; Vascular Endothelial Growth Factor A; Vitreoretinal Surgery; Vitreous Body

Angiogenin serum levels were measured in a large group of type 1 diabetic young patients, looking at whether increased Angiogenin concentrations are associated with long-term glycemic control and microvascular complications.. Four groups of patients were compared to 223 age- and sex- matched healthy controls: 196 type 1 diabetic patients (age range 3-24 years, onset of diabetes before the age of 12 years; duration of disease longer than 2 years), without microvascular complications were divided into three groups on the basis of age (group 1, n = 37, age < 6 years; group 2, n = 71, age 6-12 years; group 3, n = 88, age > 12 years); 53 adolescents and young adults (age 16.1-29.7 years) with diabetic microvascular complications (background, preproliferative or proliferative retinopathy, albumin excretion rate 20-200 microg min-1) (group 4).. Angiogenin serum levels were significantly increased in diabetic pre-school and pre-pubertal children, and particularly elevated in pubertal subjects compared with age- and sex-matched controls. Adolescents and young adults with microvascular complications had very high angiogenin concentrations. One-year mean HbA1c values were correlated with angiogenin levels (r = 0.389; p < 0.01). In poorly controlled diabetics (HbA1c > 10%), long-term (2 years) improvement of glycemic control determined a significant reduction of angiogenin concentrations in both pre-school and pre-pubertal children as well as in pubertal youngsters.. Angiogenin serum concentrations are increased in diabetic children even before puberty. Severity of microvascular complications is associated with markedly increased angiogenin serum levels. Long-term tight glycemic control determines a consistent reduction of angiogenin concentrations.

Topics: Adolescent; Adult; Case-Control Studies; Child; Child, Preschool; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Diabetic Retinopathy; Female; Glycated Hemoglobin; Humans; Male; Ribonuclease, Pancreatic

The vitreous levels of angiogenin, which is a potent blood vessel-inducing protein, were measured to determine their association with proliferative diabetic retinopathy (PDR). Undiluted vitreous fluid specimens were collected from 30 eyes with PDR at the time of vitrectomy. A sandwich enzyme-liked immunosorbent assay was then used to quantitate the levels of angiogenin. As a control we determined the levels in the specimens from 21 patients with proliferative vitreoretinopathy (PVR) and 4 patients with idiopathic macular epiretinal membrane (IERM). The average angiogenin level in the eyes with PDR was 43.7 ng/ml, and no significant difference was observed among PDR, PVR and their reoperation cases. In the category of IERM, the mean concentration of angiogenin was 2.1 ng/ml, which was significantly lower than that of the PDR and PVR cases. Our study thus demonstrated a significant increase in the vitreous angiogenin levels in eyes with PDR, PVR and those undergoing reoperation for these conditions in comparison to eyes with IERM. We therefore postulated that the elevated angiogenin levels thus reflected a breakdown of the blood-ocular barrier in eyes with PDR and PVR.

Topics: Adult; Aged; Angiogenesis Inducing Agents; Blood-Retinal Barrier; Diabetic Retinopathy; Enzyme-Linked Immunosorbent Assay; Female; Humans; Macular Degeneration; Male; Middle Aged; Proteins; Retinal Neovascularization; Ribonuclease, Pancreatic; Vitreoretinopathy, Proliferative; Vitreous Body