Mounting evidence suggests that immunological mechanisms play a fundamental role in the pathogenesis of diabetic retinopathy (DR) and diabetic macular edema (DME). Upregulation of cytokines and other proinflammatory mediators leading to persistent low-grade inflammation is believed to actively contribute to the DR-associated damage to the retinal vasculature, inducing breakdown of the blood-retinal barrier, subsequent macular edema formation, and promotion of retinal neovascularization. This review summarizes the current knowledge of the biological processes providing an inflammatory basis for DR and DME. In addition, emerging therapeutic approaches targeting inflammation are discussed, including blockade of angiopoietin 2 and other molecular targets such as interleukin (IL)-6, IL-1β, plasma kallikrein, and integrins.

The role of inflammation in diabetic eye disease

Diabetic retinopathy (DR) is a diabetic complication which affects retinal function and results in severe loss of vision and relevant retinal diseases. Retinal vascular dysfunction caused by multifactors, such as advanced glycosylation end products and receptors, pro-inflammatory cytokines and chemokines, proliferator-activated receptor-γ disruption, growth factors, oxidative stress, and microRNA. These factors promote retinal endothelial dysfunction, which results in the development of DR. In this review, we summarize the contributors in the pathophysiology of DR for a better understanding of the molecular and cellular mechanism in the development of DR with a special emphasis on retinal endothelial dysfunction.

/pdf/endothelial-dysfunction-in-diabetic-retinopathy-4txyaslnb8.pdf

Endothelial Dysfunction in Diabetic Retinopathy.

Adiponectin, one of the adipose-derived hormone with metabolic activity, has been reported to conversely affect angiogenesis of endothelial cells in vitro. The previous study in animal models has demonstrated that adiponectin has a protective role in retinal vascular injury following pathological stimuli. However, clinical research regarding the relationship between plasma adiponectin level and diabetic retinopathy (DR) are inconclusive. The aim of this study was to investigate the effect of adiponectin on high glucose-induced retinal angiogenesis and its association with autophagy by using rhesus choroid-retinal endothelial (RF-6A) cells as a model. We found that cell vitality decreased and cell migration and tube formation increased in the high-glucose group. Treatment with adiponectin or 3-methyladenine (3-MA, an autophagy inhibitor) increased cell viability and inhibited cell migration and tube formation. In the high-glucose group, the protein expression of Bax and apoptosis rate of cells increased and the expression of Bcl-2 decreased, whereas treatment with adiponectin or 3-MA reversed these results. Autophagy was activated in the high-glucose group to present as more LC3B fluorescent dots and higher expressions of LC3B, Atg5 proteins as well as lower expression of p62. Treatment with adiponectin or 3-MA inhibited autophagy by promoting the expression of p-PI3K, p-AKT, and p-mTOR when compared with the high-glucose group. The results of this study suggested that adiponectin inhibits high glucose-induced angiogenesis of RF/6A cells by inhibiting autophagy, and promotion of the PI3K/AKT/mTOR pathway might be involved in the anti-autophagy activities of adiponectin.

Adiponectin inhibits high glucose-induced angiogenesis via inhibiting autophagy in RF/6A cells.

Background Diabetic retinopathy is one of the important complications of diabetes. In major cases, diabetic retinopathy is unnoticed until the irreversible damage to eye occurs and leads to blurred vision and, eventually, blindness. Objective The pathogenesis and diagnosis of diabetic retinopathy are very complex and not fully understood. Currently, well-established laser techniques and medications are available, but these treatment options have their own shortcomings on biological systems. Biomarkers can help to overcome this problem due to easy, fast and economical options for diagnosis of diabetic retinopathy. Methods The search terms used were "Diabetic retinopathy", "Biomarkers in diabetic retinopathy", "Novel biomarkers in diabetic retinopathy" and "Potential biomarkers of diabetic retinopathy" by using different scientific resources and databases like EBSCO, ProQuest, PubMed and Scopus. Eligibility criteria included biomarkers involved in diabetic retinopathy in the detectable range. Exclusion criteria included the repetition and duplication of the biomarker in diabetic retinopathy. Results Current review and literature study revealed that biomarkers of diabetic retinopathy can be categorized as inflammatory: tumor necrosis factor-α, monocyte chemoattractant protein-1, transforming growth factor- β; antioxidant: nicotinamide adenine dinucleotide phosphate oxidase; nucleic acid: poly ADP ribose polymerase- α, Apelin, Oncofetal; enzyme: ceruloplasmin, protein kinase C; and miscellaneous: erythropoietin. These biomarkers have a great potential in the progression of diabetic retinopathy hence can be used in the diagnosis and management of this debilitating disease. Conclusion Above mentioned biomarkers play a key role in the pathogenesis of diabetic retinopathy; hence they can also be considered as potential targets for new drug development.

Potential Biomarkers in Diabetic Retinopathy.

Aim To investigate the regulation of vascular endothelial growth factors (VEGF) and pigment epithelium-derived factor (PEDF) expression by autophagy in retinal pigment epithelium (RPE) cells on exposure to hypoxia. Methods ARPE-19, an RPE cell line, was treated as following: the control group was kept in a normoxic incubator; the hypoxia group was incubated in a hypoxic incubator with 1% O2/5% CO2/94% N2 for 24h; the hypoxia + 3-methyladenine (3-MA) group was pretreated with 10 mmol/L 3-MA for 1h and then in the hypoxic incubator for 24h; and the hypoxia + chloroquine (CQ) group was pretreated with 50 µmol/L CQ for 1h and then in the hypoxic incubator for 24h. The morphology and ultrastructure of the cells was observed by an inverted microscope or a transmission electronic microscope (TEM). Western blot was performed to assay the expression of autophagy-associated markers, including microtubule associated protein 1 light chain 3 B (LC3B), Beclin-1, Atg5 and p62. The concentration of VEGF and PEDF in the culture supernatant was determined by ELISA, and the ratio of VEGF/PEDF was calculated. Results There were no obvious differences in cell morphology among different groups and autolysosomes could be observed in the cytoplasm in all groups. Compared to the control cells, the LC3B-II/I ratio and levels of Beclin-1 and Atg5 were significantly increased and p62 level was significantly decreased in the hypoxia group. With the increase of VEGF and decrease of PEDF concentration, the VEGF/PEDF ratio was significantly increased in the hypoxia group compared to the control cells. The LC3B-II/I ratio was significantly reduced by 3-MA treatment and increased by CQ treatment. The expressions of Beclin-1 and Atg5 were significantly reduced by 3-MA or CQ treatment, while expression of p62 was increased in the 3-MA or CQ treated cells. The concentration of VEGF was significantly decreased and PEDF increased, thereby the VEGF/PEDF ratio was decreased in the hypoxia + 3-MA group and hypoxia + CQ group compared with that in the hypoxia group. Conclusion Hypoxia leads to elevated autophagy in RPE cells, and expression of VEGF and PEDF might be regulated by autophagy on exposure to hypoxia to further participate in regulating the formation of retinal neovascularization.

Autophagy: a new mechanism for regulating VEGF and PEDF expression in retinal pigment epithelium cells.

Tumor necrosis factor-α and diabetic retinopathy: Review and meta-analysis.

The relationship between the role of VEGF and autophagy in the process of retinal angiogenesis is still unclear. In this study, we explored this issue by using the mouse retinal vascular endothelial cell (RVEC) as a model. RVECs were divided into the following groups: control, hypoxia (H), 3-methyladenine (3-MA) + H, VEGF + H, 3-MA + VEGF+H, anti-VEGF antibody + H, 3-MA+ anti-VEGF antibody + H. We then examined activation of autophagy by detecting formation of autophagosomes with transmission electron microscopy (TEM) and by counting the number of green fluorescent protein-positive (GFP+) puncta in RVECs. The turnover of microtubule associated protein 1 light chain 3 B (LC3B) and VEGF were examined by western blot. Cell migratory capacity was measured with wound healing assay and transwell assay. The capillary formation assay was performed to investigate the angiogenic capacity. Hypoxia led to an increased number of autophagosome and of the GFP+ puncta, an increased ratio of LC3B-II/I and enhanced migratory and capillary-formation capacities of RVECs. Pre-treatment with 3-MA attenuated activation of autophagy and abrogated the enhanced cell migration and capillary formation under hypoxia. Exposure to VEGF significantly increased migratory and capillary formation capacities of RVECs under hypoxia and 3-MA decreased VEGF-induced angiogenesis without its expression. Formation of autophagosome, the number of GFP+ puncta of RVECs and expression of LC3B-II/I were both elevated in cells treated with anti-VEGF antibody and these effects were partially inhibited by 3-MA pretreatment. Our present data may identify autophagic response as a novel target for enhancing the therapeutic efficacy of angiogenesis inhibitors.

/pdf/manipulation-of-autophagy-a-novelly-potential-therapeutic-1arc7wvx32.pdf

Manipulation of autophagy: a novelly potential therapeutic strategy for retinal neovascularization

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Tumor necrosis factor-α and diabetic retinopathy: Review and meta-analysis.

Manipulation of autophagy: a novelly potential therapeutic strategy for retinal neovascularization