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

糖尿病视网膜病变视网膜神经细胞损伤的分子机制及新的治疗方式

基本信息

批准号：
17591819
负责人：
YAMASHITA Hidetoshi
金额：
$ 2.24万
依托单位：
Yamagata University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17591819/
关键词：
Diabetic retinopathy Retinal neuronal cell Retinal vessel Metabolic abnormalities of glucose VEGF Protection of Neuronal cells Activin A Apoptosis 糖尿病 DGKα PKCβ1

项目摘要

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

糖尿病视网膜病变仍然是世界范围内工作年龄成人获得性视力丧失的一个重要原因。随着糖尿病患者数量的增加，糖尿病视网膜病变的发病率也在增加，为减少糖尿病视网膜病变导致的获得性视力丧失，必须发展视网膜神经细胞保护的新策略。为了探究这一策略，我们研究了视网膜神经元细胞损伤的分子机制并抑制这一过程。我们阐明了蛋白激酶C β (PKC β)和二酰基甘油激酶（DGK）的激活通过影响视网膜神经元细胞参与糖尿病视网膜病变的发生和进展。暴露于高葡萄糖水平导致二酰基甘油（DAG）合成从头增加，其激活视网膜神经元细胞中的PKC β3并加速血管内皮生长因子（VEGF）的产生。DGK催化DAG磷酸化生成磷脂酸（PA），控制DAG水平，并在高糖环境下受到刺激。我们通过2种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VEGF的表达，明确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过程中，纤维血管膜的形成是重要的，透明细胞参与了这一过程。我们观察到炎症因子（IL-1 α、β3、TNF-α）刺激了VEGF和白细胞介素6 （IL-6）的表达。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作用。采用视网膜母细胞瘤（retinoblastoma， RB）细胞系研究activinA对视网膜神经元细胞的影响。以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的细胞质组分。激活ina刺激后，荧光素酶测定证实了信号转导途径。激活素A信号可诱导RB细胞凋亡。综上所述，高血糖和/或多种细胞因子可能与视网膜神经元细胞损伤包括凋亡有关。抑制细胞凋亡可能是保护视网膜神经元细胞的靶点。少