Study on file RAGE signaling in vascular cells - a novel mechanism of the development of diabetic vascular complications

血管细胞RAGE信号研究——糖尿病血管并发症发生的新机制

基本信息

批准号：
13670113
负责人：
YONEKURA Hideto
金额：
$ 2.24万
依托单位：
Kanazawa University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
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/grant/KAKENHI-PROJECT-13670113/
关键词：
diabetic complications transgenic mouse advanced glycation endproducts (AGE)alternative splicing endogenous soluble receptor receptor for AGE (RAGE)esRAGE gene knockout mouse receptor for AGE (RAGE)gene knockout mous advanced glycat

项目摘要

In this research, we provide the first direct in vivo evidence that interactions between advanced glycation end products (AGE) and their receptor, RAGE, lead to diabetic vascular derangements. We also found the presence of a cytoprotective secretory form of RAGE (endogenous secretory RAGE, esRAGE) in human and identified new RAGE ligands, which are abundantly present in human circulation.(1) We created transgenic mice that overexpress human RAGE in vascular cells. The diabetic RAGE transgenic mice exhibited an accelerated development of diabetic nephropathy. This transgenic mouse will be a useful animal model that shows the renal changes seen in humans.(2) We also created transgenic mice that overexpress human RAGE in the heart and obtained evidence suggesting that the AGE and RAGE could play an active role in the development of diabetes-induced cardiac dysfunction.(3) We created RAGE gene-knockout mice and showed that the advanced diabetic nephropathy was significantly suppressed in the diabetic knockout mice.(4) We demonstrated that human vascular endothelial cells (EC) and pericytes express a novel splice variant encoding a novel secretory form of RAGE (esRAGE). The AGE induction of ERK phosphorylation and vascular endothelial growth factor in EC and of the growth and cord-like structure formation of EC was perfectly abolished by this RAGE variant, indicating that esRAGE is cytoprotective against AGE. The findings may contribute to our understanding of the molecular basis for the diversity of cellular responses to AGE and for individual variations in susceptibility or resistance to diabetic vascular complications.(5) We identified glyceraldehyde- and glycolaldehydee-derived AGE as new RAGE ligands. The AGE fractions increased VEGF mRNA levels in human EC as well as cell growth. These results suggested that glyceraldehyde- and glycolaldehyde-derived AGE participate in vascular injury in diabetes.

在这项研究中，我们提供了第一个直接的体内证据，即先进的糖基化终产物（年龄）及其受体愤怒之间的相互作用导致糖尿病血管危险。我们还发现了人类中的愤怒（内源性分泌愤怒，埃斯拉奇）的细胞保护分泌形式，并确定了新的愤怒配体，这些配体在人循环中大量存在。（1）我们创造了过表达血管细胞中人类愤怒的转基因小鼠。糖尿病愤怒转基因小鼠表现出糖尿病性肾病的加速发展。这种转基因小鼠将是一个有用的动物模型，显示人类中看到的肾脏变化。（2）我们还创建了过表达人类心脏愤怒的转基因小鼠，并获得了证据，表明年龄和愤怒可以在糖尿病诱导的心脏功能障碍的发展中发挥积极作用。（4）我们证明了人血管内皮细胞（EC）和周细胞表达了一种新型的剪接变体，编码了一种新型的分泌形式的愤怒（ESRAGE）。这种愤怒的变体完全消除了EC的ERK磷酸化和血管内皮生长因子的年龄诱导以及EC的生长和绳状结构形成的形成，这表明Esrage对年龄具有细胞保护作用。这些发现可能有助于我们理解分子基础对年龄的多样性以及对糖尿病血管并发症的易感性或抗性的各个变化的多样性。（5）我们确定了甘油醛和甘油醛和甘油醛的年龄为新的愤怒的配体。年龄分数增加了人类EC和细胞生长中的VEGF mRNA水平。这些结果表明，甘油醛和甘油醛的年龄参与糖尿病的血管损伤。

项目成果

期刊论文数量（61）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Miyakawa, T.: "Exposure of C.elegans to extremely low frequency high magnetic fields induces stress responses"Bioelectromagnetics. 22(5). 333-339 (2001)

Miyakawa, T.：“线虫暴露于极低频高磁场会诱发应激反应”生物电磁学。

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Yamamoto, Y.: "Advanced diabetic nephropathy in RAGE-overexpressing mice"Excerpta Medica International Congress Series. 1245(in press.). (2002)

Yamamoto, Y.：“RAGE 过度表达小鼠的晚期糖尿病肾病”医学摘录国际大会系列。

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Unoki H., Furukawa K., Yonekura H., Ueda Y., Katsuda S., Amano H., Nakagawara K., Mabuchi H., and Yamamoto, H.: "Cyr61 Upregulation in Vascular Smooth Muscle Cells of Spontaneously Hypertensive Rats"Lab. Invest.. in press. (2003)

Unoki H.、Furukawa K.、Yonekura H.、Ueda Y.、Katsuda S.、Amano H.、Nakakawara K.、Mabuchi H. 和 Yamamoto, H.：“自发性高血压大鼠血管平滑肌细胞中的 Cyr61 上调

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Miura J. et al.: "AGE dowuregulation of monocyte expression of RAGE mRNA and its association with diabetic complications in type 1 diabetes"J Diabetes Complications. (in press). (2003)

Miura J. 等人：“AGE dowuregulation of mononuclear expression of RAGE mRNA and its Association with Diabetes Complications in Type 1 Diabetes”J Diabetes Complications。