# Diabetic Retinopathy and Ocular Melanoma: How Far We Are?
## 3 Diabetic Retinopathy, Angiogenesis and Anti-Angiogenic Therapy
In DR, RPE cells also release inflammatory cytokines, chemokines and angiogenic factors (e.g., IL6, IL8, MCP-1, TGF\(\beta\) and VEGF), which are mainly responsible for the development of the disease [91]. Monocyte chemoattractant protein-1 (MCP-1) influences retinal leukocyte infiltration as well as VEGF manifestation [92; 93]. The influence of MCP-1 on BRB rupture was studied in vivo. MCP-1 knockout mice injected with streptozotocinol to induce diabetes showed low retinal vascular leakage, monocyte infiltration and retinal microglial stimulation [94]. It has been demonstrated that in DR, TNF\(\kappa\) (NF-\(\kappa\)B-transcriptionally regulated cytokine secreted by macrophages and T cells) potentiate leukostasis, lead to BRB disruption and stimulate adhesion molecules, leukocyte production, apoptosis, monocyte chemoattraction and growth factors among other inflammatory mediators [82; 95]. Thus, anti-TNF\(\kappa\) therapy tested in diabetic mice caused decreased loss of pericytes and capillary degeneration, and in humans this therapy visually improved diabetic macular edema [96]. Several inflammatory cytokines in the interleukin (IL) category also influence DR. IL6 has been shown to induce vascular permeability, angiogenesis and manifestation of VEGF in this disease [97; 98; 99]. In addition to the angiogenic function, IL8 is also chemoattractive [100]. IL1\(\beta\) also has a crucial role in DR. It is generated by macrophages and activates the transcription factor NF-\(\kappa\)B. This factor commands the transcription of inflammatory cytokines (e.g., IL6 and IL8) in RPE cells. This cytokine also boosts angiogenesis and neovascularization. In an in vivo study in a diabetic mice model it was shown that the exclusion of receptors protected the animals from the evolution of DR [101; 102; 103]. Toll-like receptors (TLRs) are a collection of receptors that respond to endogenous microbes and ligands and thus manifest in the various retinal cells. In DR, these receptors are activated through intracellular signalling cascades, which lead to the generation of proinflammatory cytokines, control costtimulatory molecules, provoke oxidative DNA damage and stimulate angiogenic growth factors. High mobility group protein B1 (HMGB1) allows nucleosome stabilization and transcription of the TLR2 and TLR4 binding genes and the receptor for advanced glycation end products. This protein is discharged by monocytes, activated macrophages, natural killer cells, mature dendritic cells and also endothelial cells. In addition, it has the same function as a proinflammatory cytokine [104; 105; 106]. HMGB1 is manifested through the various cells in the retina, also promoting the manifestation of VEGF, TNF\(\alpha\), MCP1 and ICAM-1 and stimulating vasculopathy [107; 108; 109]. DR patients have high HMGB1 levels [107]. In vitro studies on glial cells have shown that HMGB1 favours cytotoxic effects and also promotes the death of pericytes and endothelial cells [110]. Hyperglycaemia in RPE cells promotes the generation of HMGB1 and consequently the generation of NF-\(\kappa\)B and VEGF. In addition, in retinal endothelial cells, hyperglycaemia also induces the manifestation of TLR2 and TLR4 and the activation of NF-\(\kappa\)B, promoting the production of IL8, TNF\(\alpha\), MCP1 and adhesion molecules. The expression of the receptor for advanced glycated end products TLR2, TLR4 and HMGB has been studied in vivo in the retina of mice with type 2 diabetic, and it has been shown that HMGB1 stimulates the generation of VEGF via TLR4 in RPE cells and also cytokines via TLR2 and TLR4 in endothelial cells [111; 112]. In TLR7 knockout mice, it has been shown that this receptor induces inflammatory response in DR [113]. Another in vitro study also demonstrated the role of P2X7 purinergic receptors.