Molecular Mechanisms of Damage to Retinal Neuronal Cells in Diabetic Retinopathy and New Therapeutic Modalities

糖尿病视网膜病变仍然是全球工作年龄成人获得性视力丧失的重要原因。糖尿病视网膜病变的发病率沿着糖尿病患者的增加而增加，迫切需要开发保护视网膜神经细胞的新策略，以减少糖尿病视网膜病变导致的获得性视力丧失患者的数量。为了探讨这一策略，我们研究了糖尿病视网膜神经细胞损伤的分子机制，阐明了蛋白激酶C β（PKC β）和甘油二酯激酶（DGK）的激活通过影响视网膜神经细胞参与糖尿病视网膜病变的发生和发展。高糖暴露导致二酰甘油（diacylglycerol，DAG）合成重新增加，从而激活视网膜神经细胞中的PKC β 3，促进血管内皮生长因子（vascular endothelial growth factor，VEGF）的产生。DGK催化剂 关于我们 将DAG磷酸化为磷脂酸（PA），控制DAG水平，并在暴露于高糖后刺激。我们通过VEGF在两种类型的视网膜母细胞瘤细胞和作为动物模型的链脲佐菌素诱导的糖尿病大鼠的视网膜中的表达来阐明DGK a与糖尿病视网膜病变的发病机制有关。在糖尿病视网膜病变的发病机制中，纤维血管膜的形成是重要的，透明细胞参与了这一过程。我们观察了炎症细胞因子（IL-1 α和β 3，TNF-α）对VEGF和白细胞介素6（IL-6）表达的刺激作用。视网膜神经元细胞死亡的机制：ActivinA在眼内表达，对视网膜病变有一定的作用。使用视网膜母细胞瘤（RB）细胞系研究激活素A对视网膜神经元细胞的作用。RB细胞系用作未分化的视网膜细胞，表达激活素受体和激活素的细胞质组分。在激活素A刺激后，通过荧光素酶测定证实了信号转导途径。激活素A信号显示诱导RB细胞中的凋亡。综上所述，高糖条件和/或各种细胞因子可能与视网膜神经元细胞损伤（包括凋亡）有关。抑制凋亡可能是保护视网膜神经细胞的靶点。少

Diabetic retinopathy remains a significant cause of acquired visual loss in working-age adults worldwide. The incidence of diabetic retinopathy increases along with the increase of the number of diabetes mellitus patients, and it is mandatory to develop the new strategy of the protection of retinal neuronal cells to decrease the number of acquired visual loss patients due to diabetic retinopathy. To inquire this strategy, we have investigated the molecular mechanisms of the damage to retinal neuronal cells and to inhibit this process.We clarified that the activation of protein kinase C β (PKC β ) and diacylglycerol kinase (DGK) contribute to the development and progression of diabetic retinopathy by affecting the retinal neuronal cells. The exposure to the high glucose level leaded to the de novo increase in the synthesis of diacylglycerol (DAG), which activated PKC β3 in the retinal neuronal cells and accelerated the production of vascular endothelial growth factor (VEGF). DGK catalyz … More es phosphorylation of DAG to phosphatidic acid (PA), controls DAG levels, and was stimulated after the exposure to the high glucose. We clarified that DGK a was related to the pathogenesis of diabetic retinopathy through VEGF expression both in 2 types of retinoblastoma cells and the retina of streptozotocin-induced diabetic rats as an animal model. In the pathogenesis of diabetic retinopathy, fibro-vascular membrane formation is important, and hyalocytes are involved in this process. We observed the expression of VEGF and interleukin6 (IL-6) was stimulated by the inflammatory cytokines (IL-1 α and β3, TNF-α ).The mechanisms of retinal neuronal cell death : ActivinA is expressed in eyes and exerts certain effects on retinopathy. The effects of activinA on retinal neuronal cells were investigated using retinoblastoma (RB) cell lines. RB cell lines were used as the undifferentiated retinal cells, expressed activin receptors and cytoplasmic components for activin. The signal transduction pathway was confirmed by using Luciferase assay after the stimulation of activinA. Activin A signal was shown to induce apoptosis in RB cells. Taken together, high glucose condition and/or various cytokines may be related to the retinal neuronal cell damage including apoptosis. The inhibition of apoptosis may be the target to protect retinal neuronal cells. Less