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劳动年龄成年人获得性视力丧失的重要原因。随着糖尿病患者数量的增加，糖尿病视网膜病变的发生率也随之增加，开发保护视网膜神经细胞的新策略势在必行，以减少因糖尿病视网膜病变而导致的获得性视力丧失患者的数量。为了探讨这一策略，我们对视网膜神经细胞损伤的分子机制进行了研究，并对这一过程进行了抑制。我们阐明了蛋白激酶Cβ(PKCβ)和二酰甘油激酶(DGK)的激活通过影响视网膜神经细胞而参与糖尿病视网膜病变的发生和发展。高糖暴露导致视网膜神经细胞合成二酰甘油增加，从而激活视网膜神经细胞中的蛋白激酶Cβ3，促进血管内皮生长因子的产生。DGK催化…DAG的ES磷酸化水平较高，控制DAG的水平，并在高糖环境下受到刺激。我们通过在两种类型的视网膜母细胞瘤细胞和链脲佐菌素诱导的糖尿病大鼠视网膜中表达血管内皮生长因子，阐明DGKa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。观察炎性细胞因子(IL-1、α、β-α)刺激视网膜内血管内皮生长因子和白介素6(IL-6)的表达。以视网膜母细胞瘤(RB)细胞株为研究对象，研究了ActivinA对视网膜神经细胞的作用。Rb细胞系作为未分化的视网膜细胞，表达激活素受体和激活素胞浆成分。经激动素A刺激后，用荧光素酶分析确定该信号转导途径。激活素A信号可诱导Rb细胞凋亡。综上所述，高糖状态和/或多种细胞因子可能与包括细胞凋亡在内的视网膜神经细胞损伤有关。抑制细胞凋亡可能是保护视网膜神经细胞的作用靶点。较少

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