糖化蛋白レセプター(RAGE)情報伝達系の解明: 糖尿病性血管病変発生の新機構

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Author: 米倉, 秀人ほか

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Publication date: 2004-04-13

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Note (General)：: 金沢大学大学院・医学系研究科本研究の目的は、糖尿病性血管合併症発生の原因物質と考えられる後期糖化反応生成物(advanced glycation endproducts,以下AGE)が、血管細胞上の受容体(糖化蛋白レセプター;receptor for AGE,以下RAGE)に結合して、血管合併症を引...

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Material Type: 文書・図像類
Title: 糖化蛋白レセプター(RAGE)情報伝達系の解明: 糖尿病性血管病変発生の新機構
Author/Editor: 米倉, 秀人
Yonekura, Hideto
Author Heading: 米倉, 秀人
Yonekura, Hideto
Publication Date: 2004-04-13
Publication Date (W3CDTF): 2004-04-13
Alternative Title: Study on file RAGE signaling in vascular cells - a novel mechanism of the development of diabetic vascular complications
Periodical title: 平成14(2002)年度科学研究費補助金基盤研究(C) 研究報告書概要 = 2002 Fiscal Year Final Research Report Summary
No. or year of volume/issue: 2001 – 2002
Volume: 2001 – 2002
Pages: 3p.-
Text Language Code: jpn
Subject Heading: diabetic complications
advanced glycation endproducts(AGE)
receptor for AGE(RAGE)
alternative splicing
endogenous soluble receptor
gene knockout mouse
esRAGE
advanced glycation endproducts (AGE)
receptor for AGE (RAGE)
gene knockout mous
advanced glycation endproducts
RAGE
splice variants
gene targeting
Target Audience: 一般
Note (General): 金沢大学大学院・医学系研究科
本研究の目的は、糖尿病性血管合併症発生の原因物質と考えられる後期糖化反応生成物(advanced glycation endproducts,以下AGE)が、血管細胞上の受容体(糖化蛋白レセプター;receptor for AGE,以下RAGE)に結合して、血管合併症を引き起すまでの分子機構を解明することである。本研究で、研究代表者らは、以下の成果を得た。1.血管細胞でRAGEを高発現するトランスジェニックマウスを用いた解析から、糖尿病腎症の発生・進展におけるAGE-RAGE系の機能的役割を初めて個体レベルで明らかにした。2.RAGEトランスジェニックマウスより分離した初代培養心筋細胞へのAGE-RAGE系の影響を解析した結果、AGE-RAGE系が心筋細胞のカルシウムホメオスタシスに彰響を与えうることが示された。3.RAGE遺伝子ノックアウトマウスを作製した。RAGEノックアウトマウスは見かけ上正常に誕生・生育し、各臓器に形態学的異常は認められなかったが、マウスに糖尿病を誘導したところ、糖尿病野生型マウスと比較して腎症の軽液が認められた。4.天然の可溶型RAGE蛋白をコードするcDNAをヒト初代培養血管内皮細胞より分離、この可溶型受容体をesRAGE(endogenous secretory RAGE)と命名した。5.esRAGEの血管細胞での役割を解析し、esRAGEがAGEに対し血管保護作用を有することを明らかにした。6.esRAGE ELISA定量系を開発して可溶型RAGE発現量の差と血管合併症罹患との相関を解析したところ、網膜症あるいは腎症罹患者で血中esRAGE量が低い傾向を見い出し、血管合併症発症のリスク予知法開発の可能性を示した。7.glyceraldehydeおよびglycolaldehyde由来のAGEが、RAGEの新しいリガンドであり、ヒト血液中のRAGE結合性AGEの主要成分であることを明らかにした。8.AGE-RAGEの結合を阻害するRAGE由来ペプチドを同定し、AGE-RAGE系を標的とした血管合併症の新しい予防・治療法開発の可能性を示した。
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.
研究課題/領域番号:13670113, 研究期間(年度):2001 – 2002
出典：「糖化蛋白レセプター(RAGE)情報伝達系の解明-糖尿病性血管病変発生の新機構-」研究成果報告書　課題番号13670113（KAKEN：科学研究費助成事業データベース（国立情報学研究所））（https://kaken.nii.ac.jp/ja/report/KAKENHI-PROJECT-13670113/136701132002kenkyu_seika_hokoku_gaiyo/)を加工して作成
DOI: 10.24517/00063773
Access Restrictions: 限定公開
Related Material: https://kaken.nii.ac.jp/ja/search/?kw=80240373
https://kaken.nii.ac.jp/ja/grant/KAKENHI-PROJECT-13670113/
https://kaken.nii.ac.jp/ja/report/KAKENHI-PROJECT-13670113/136701132002kenkyu_seika_hokoku_gaiyo/
Data Provider (Database): 国立情報学研究所 : 学術機関リポジトリデータベース（IRDB）（機関リポジトリ）
https://irdb.nii.ac.jp
Original Data Provider (Database): 金沢大学 : 金沢大学学術情報リポジトリKURA