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Cell Biology of Diabetic Retinopathy

糖尿病视网膜病变的细胞生物学

基本信息

批准号：
13470369
负责人：
ISHIBASHI Tatsuro
金额：
$ 5.12万
依托单位：
Kyushu University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13470369/
关键词：
Diabetic Retinopathy VEGF Cell Biology KDR PPARγ SU5416 PEDF Hyalocyte 組織因子 Egr-1 pioglitazone Sp1 Sp3 インスリン抵抗性 MAP kinase

项目摘要

Diabetic retinopathy has been recognized as a major cause of blindness especially in the working age population. Although VEGF has been reported to involved in the initiation and progression of diabetic retinopathy, the precise mechanisms including its receptors and cell signaling remained largely unclear. The aim of the study of this period was to elucidate the precise mechanisms of VEGF intiating and progressing diabetic retinopathy. It was widely accepted that diabetic retinopathy has three fundamental vascular disorders: vascular hyperpermeability, micro-vascular occlusion, and angiogenesis. We initially examined the causal relationships between VEGF-KDR system and the vascular hyperpermeability using the in vitro double chamber system. We confirmed that VEGF-E, a VEGFR-2 (KDR) specific ligand, could increase the vascular permeability, while PlGF, a VEGFR-1 (flt-1) specific ligand, could not. We thus suggested that VEGF regulated the vascular hyperpermeability mainly through KDR. W … More e also confirmed that VEGF could increase the expression of TF, the initiator of external coagulation cascade, in retinal capillary endothelial cells both in vivo and in vitro. In addition, we demonstrated that VEGF-induced TF expression was mediated through p44/p42 MAP kinase and the transcription factor Egr-1. These findings supported the possibility that VEGF-KDR system could promote micro-vascular occlusion. Since VEGF-KDR system has been recognized to regulate ocular angiogenesis, VEGF-KDR system plays a pivotal role to initiate and progress three fundamental vascular disorders in diabetic retinas. From these findings, we hypothesize the suppression of the VEGF-KDR system is the key strategy to inhibit the blindness due to diabetic retinopathy. We next revealed that PPARγ ligands could suppress the KDR gene expression through the suppression of interaction between Sp1/Sp3 and its promoter region. We also demonstrated that PPARγ ligands could suppress rodent angiogenesis models in vivo. These findings showed that PPARγ ligands are hopeful drugs to treat diabetic retinopathy through the inhibition of VEGF and its receptor system as well as SU5416 which is one of KDR-selective tyrosine kinase inhibitors.We also examined the expression of pigment epithelium-derived growth factor (PEDF), known as one of the angiogenesis inhibitors, using cultured retinal cells and hyalocytes. PEDF was broadly expressed by cultured cells such as glial cells, pericytes and hyalocytes in addition to retinal pigment epithelial cells. These results suggested that many cell types are involved in the regulation of intraocular angiogenesis. In addition, hyalocytes might play an important role to keep the vitreous cavity as avascular area through the function of PEDF. Less

糖尿病视网膜病变已被认为是失明的主要原因，特别是在工作年龄人群中。虽然VEGF参与了糖尿病视网膜病变的发生和发展，但其受体和细胞信号转导等确切机制仍不清楚。本研究旨在阐明VEGF在糖尿病视网膜病变中的作用机制。糖尿病视网膜病变有三种基本的血管病变：血管通透性过高、微血管闭塞和血管生成。我们初步研究了VEGF-KDR系统与血管通透性增高之间的因果关系，使用体外双室系统。我们证实VEGF-E（VEGFR 2（KDR）特异性配体）可增加血管通透性，而PlGF（VEGFR 1（flt-1）特异性配体）则不能。因此，我们认为VEGF主要通过KDR调节血管通透性。W ...更多信息进一步证实了VEGF在体内和体外均能增加视网膜毛细血管内皮细胞TF的表达，TF是体外凝血级联反应的起始因子。此外，我们证明VEGF诱导的TF表达是通过p44/p42 MAP激酶和转录因子Egr-1介导的。这些结果支持VEGF-KDR系统促进微血管闭塞的可能性。由于VEGF-KDR系统被认为是调节眼部血管生成的重要系统，因此VEGF-KDR系统在糖尿病视网膜三种基本血管病变的发生和发展中起着关键作用。根据这些发现，我们推测抑制VEGF-KDR系统是抑制糖尿病视网膜病变致盲的关键策略。我们进一步研究发现，PPARγ配体可以通过抑制Sp1/Sp3与其启动子区的相互作用来抑制KDR基因的表达。我们还证明了PPARγ配体可以抑制啮齿类动物体内血管生成模型。这些结果表明，PPARγ配体通过抑制VEGF及其受体系统以及KDR选择性酪氨酸激酶抑制剂SU 5416，有望成为治疗糖尿病视网膜病变的药物。除视网膜色素上皮细胞外，PEDF还广泛表达于培养的细胞，如胶质细胞、周细胞和透明细胞。这些结果表明，许多细胞类型参与了眼内血管生成的调节。玻璃体细胞可能通过PEDF的作用，在维持玻璃体腔的无血管性方面发挥重要作用。少