The pathological investigation of proliferative diabetic retinopathy based on the control of retinal pericytes

基于视网膜周细胞控制的增殖性糖尿病视网膜病变的病理学研究

基本信息

批准号：
12470363
负责人：
TAKAGI Hitoshi
金额：
$ 9.02万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12470363/
关键词：
endothelial cells pericytes angiopoietin 2 AT 1 receptor angiotensin diabetic retinopathy retinal edema PDGF-receptor 内皮-周皮細胞間制御機構 pericyte loss アンジオテンシン ATI阻害薬アンジオポエチン1 ストレプトゾトシン糖尿病ラットアンジオポイエチン1 Tie2 VEGFファミリーアンジオポイエチ

项目摘要

In this research, we investigated the control mechanism of retinal endothelial cells and pericytes, and aimed at a new therapeutic development of intraocular vascular proliferative diseases. In a diabetic retinopathy, pericyte loss is known to cause microaneuiysms and vascular hyperpermiability. In streptozotocine-induced diabetic rats, angiopoietine 2 is proved to be highly expressed after 6 months from onset of diabetes by RT-PCR analyses, and pericyte loss is observed by in situ hybridization and double immune staining analyses in the retinal cite where angiopoietine 2 is expressed. (IOVS 2003;44;393-402). In the eyes of diabetic retinopathy, angiotensin 2 selectively potentiates angiopoietine 2 in retinal endothelial cells, and this suggests the role of angiotensin 2 in the relation between endothelial cells and pericytes. (Diabetes 2001;50;867-875). These results are highly evaluated as a basic data on clinical trials, such as DIRECT study. In the next, we aimed a new therapeutic development on such vessels in which pericytes are degenerated. The injection of an antagonistic mAb against PDGFR-beta into murine neonates provides such pericyte loss of retinal vessels, and vessels of such mice are poorly remodeled and leaky. This model resembles a pathological change in diabetic retinopathy. We show that addition of recombinant modified angiopoietin 1 restored a hierarchical valculature, and also rescued retinal edema and hemorrhage in the complete absensce of pericytes. These observations demonstrate the potential of angiopoietin 1 as a new therapeutic modality for pericyte loss in diseases such as diabetic retinopathies. (JCI 2002;110;1619-28). Angiopoietin 1 and angiotensin type 1 receptor blocker are possible to be an effective drug in a diabetic retinopathy.

在这项研究中，我们研究了视网膜内皮细胞和周细胞的控制机制，并针对人类血管内血管增殖性疾病的新治疗性发育。在糖尿病性视网膜病变中，已知周细胞丧失会导致微型体积和血管过敏性。在链蛋白酶诱导的糖尿病大鼠中，通过RT-PCR分析从糖尿病发作后6个月后，血管生成素2被证明是高度表达的，并且通过原位杂交观察到周细胞损失，并且通过在Angiopoietine 2是Angiopoietine 2 Is an Angiopoietine 2 IS中通过双重免疫染色分析。表达。（IOVS 2003; 44; 393-402）。在糖尿病性视网膜病的眼中，血管紧张素2在视网膜内皮细胞中有选择地增强血管生成素2，这表明血管紧张素2在内皮细胞和周细胞之间的关系中的作用。（Diabetes 2001; 50; 867-875）。这些结果被评估为临床试验的基本数据，例如直接研究。接下来，我们针对此类船只的新治疗性发育，在该血管中，周细胞退化。将拮抗作用mAb针对PDGFR-beta注射到鼠新生儿中，可提供视网膜血管的周围损失，并且此类小鼠的血管重塑且漏水不佳。该模型类似于糖尿病性视网膜病的病理变化。我们表明，重组修饰的血管生成素1的添加恢复了分层阀门，并在周细胞完全下降中挽救了视网膜水肿和出血。这些观察结果表明，血管生成素1是糖尿病性视网膜病等疾病中周细胞丧失的一种新的治疗方式。（JCI 2002; 110; 1619-28）。血管生成素1和血管紧张素1型受体阻滞剂可能是糖尿病性视网膜病的有效药物。