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| 1.
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Yamamoto, Yasuhiko ; Kato, Ichiro ; Doi, Toshio ; Yonekura, Hideto ; Ohashi, Seiji ; Takeuchi, Masayoshi ; Watanabe, Takuo ; Sakurai, Shigeru ; Yasui, Kiyoshi ; Ralica, Petrova G ; Joynal, Abedin ; Hui, Li ; A.K.M.Azadur, Rahman ; Takasawa, Shin ; Okamoto, Hiroshi ; Yamamoto, Hiroshi
概要:
金沢大学大学院医学部医学系研究科<br />Vascular complications are what eventually threaten the lives of diabetic patients. Here we show d
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irect in vivo evidence that the interaction between advanced glycation end products (AGE), the formation of which is accelerated during prolonged hyperglycemic exposure, and a cell surface receptor for AGE (RAGE) is the major cause of such complications. We created transgenic mice that overexpress human RAGE in vascular cells and crossbred them with another transgenic line which develops insulin-dependent diabetes early after birth. The resultant double transgenic mice exhibited accelerated kidney changes compared with single transgenic littermates, and the nephropathy was ameliorated by an inhibitor of AGE formation. The AGE–RAGE system will thus be a promising target for overcoming diabetic complications.
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| 2.
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Yamamoto, Yasuhiko ; Yonekura, Hideto ; Sakurai, Shigeru ; Tanaka, Nobushige ; Hui, Li ; Khin-Mar, Myint ; Chul-Hee, Kim ; Harashima, Ai ; Osawa, Mari ; Takeuchi, Masayoshi ; Watanabe, Takuo ; Yamamoto, Hiroshi
概要:
金沢大学大学院医学部医学系研究科<br />As is diabetes itself, diabetic vasculopathy is a multifactor disease. Studies conducted in this l
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ab revealed advanced glycation endproducts (AGE) as the major environmental account for vascular cell derangement characteristic of diabetes, and the receptor for AGE (RAGE) as the major genetic factor that responds to them. AGE fractions that caused the vascular derangement were proven to be RAGE ligands. When made diabetic, RAGE-overexpressing transgenic mice exhibited the exacerbation of the indices of nephropathy, and this was prevented by the inhibition of AGE formation. We also created RAGE-deficient mice. They showed marked amelioration of diabetic nephropathy. Extracellular signals and nuclear factors that induce the transcription of human RAGE gene were also identified, which would be regarded as risk factors of diabetic complications. Through an analysis of vascular polysomal poly(A)+ RNA, we came across a novel splice variant coding for a soluble RAGE protein, and named it endogenous secretory RAGE (esRAGE). esRAGE was able to capture AGE ligands and neutralize the AGE action on endothelial cells, suggesting that this variant has a potential to protect blood vessels from diabetes-induced injury. The AGE–RAGE system should thus be regarded as a candidate molecular target for overcoming this life- and quality of life (QOL)-threatening disease.
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| 3.
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Sugihara, Takahiro ; Munesue, Seiichi ; Yamamoto, Yasuhiko ; Sakurai, Shigeru ; Akhter, Nasima ; Kitamura, Yoji ; Shiba, Kazuhiro ; Watanabe, Takuo ; Yonekura, Hideto ; Hayashi, Yasuhiko ; Hamada, Jun-ichiro ; Yamamoto, Hiroshi
概要:
The cell-surface receptor for advanced glycation end-products (RAGE) has been implicated in the development of diabetic
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vascular complications and Alzheimer's disease. RAGE has been considered to be involved in amyloid-β 1-42 (Aβ 1-42) uptake into brain. In the present study, we demonstrate that endogenous secretory RAGE (esRAGE), a decoy form of RAGE generated by alternative RNA processing, is able to inhibit Aβ 1-42 influx into mouse brain. Surface plasmon resonance and competitive binding assays revealed that human Aβ 1-42 interacted with human esRAGE within the immunoglobulin V type region. We next examined the uptake and distribution of 125I-labeled human Aβ 1-42 in various organs and body fluids of newly created mice overexpressing human esRAGE as well as RAGE-null and wild-type (WT) mice. The transition of the 125I-labeled Aβ 1-42 from circulation to brain parenchyma peaked at 30 min after the injection into WT mice, but this was significantly blunted in esRAGE-overexpressing and RAGE-null mice. Significant reduction in 125I-labeled Aβ 1-42-derived photo-stimulated luminescence were marked in ventricles, cerebral cortex, hippocampus, especially CA1 and CA3 regions, putamen, and thalamus. The results thus suggest the potential of esRAGE in protection against the development of Alzheimer's disease. © 2012 - IOS Press and the authors. All rights reserved.
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| 4.
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Sugihara, Takahiro ; Munesue, Seiichi ; Yamamoto, Yasuhiko ; Sakurai, Shigeru ; Akhter, Nasima ; Kitamura, Yoji ; Shiba, Kazuhiro ; Watanabe, Takuo ; Yonekura, Hideto ; Hayashi, Yasuhiko ; Hamada, Jun-ichiro ; Yamamoto, Hiroshi
概要:
The cell-surface receptor for advanced glycation end-products (RAGE) has been implicated in the development of diabetic
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vascular complications and Alzheimer's disease. RAGE has been considered to be involved in amyloid-β 1-42 (Aβ 1-42) uptake into brain. In the present study, we demonstrate that endogenous secretory RAGE (esRAGE), a decoy form of RAGE generated by alternative RNA processing, is able to inhibit Aβ 1-42 influx into mouse brain. Surface plasmon resonance and competitive binding assays revealed that human Aβ 1-42 interacted with human esRAGE within the immunoglobulin V type region. We next examined the uptake and distribution of 125I-labeled human Aβ 1-42 in various organs and body fluids of newly created mice overexpressing human esRAGE as well as RAGE-null and wild-type (WT) mice. The transition of the 125I-labeled Aβ 1-42 from circulation to brain parenchyma peaked at 30 min after the injection into WT mice, but this was significantly blunted in esRAGE-overexpressing and RAGE-null mice. Significant reduction in 125I-labeled Aβ 1-42-derived photo-stimulated luminescence were marked in ventricles, cerebral cortex, hippocampus, especially CA1 and CA3 regions, putamen, and thalamus. The results thus suggest the potential of esRAGE in protection against the development of Alzheimer's disease. © 2012 - IOS Press and the authors. All rights reserved.<br />Thesis of Sugihara Takahiro / 学位論文 医学甲第2227 杉原 崇大
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| 5.
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米倉, 秀人 ; Yonekura, Hideto
概要:
金沢大学医学系研究科<br />本研究の目的は、可溶型糖化蛋白受容体(receptor for AGE, RAGE)mRNAと可溶型VEGF受容体(Flt-1)mRNAを生成する選択的mRNAスプライシング/プロセシングの医学・生物学的意義
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を明らかにするとともに、その制御機構を解明して、血管新生や糖尿病血管合併症などの血管障害が関与する疾患のリスク予知・予防・治療法開発に向けた新規原理を打ち立てることである。平成17〜18年度の研究で以下の成果を得た。(i)可溶型RAGEmRNA選択的スプライシング(1)RT-PCRクローニングによりヒト可溶型RAGEに相当するマウスcDNAを分離した。(2)免疫組織化学法により、可溶型RAGEは血管、神経、膵β細胞、単球、胆管、顎下腺などを含む多くのヒト組織で発現していることを明らかにした。(3)ELISAを開発し、血液中の可溶型RAGE濃度と動脈硬化との関連を検討したところ、血中可溶型RAGE濃度は動脈硬化の進行と逆相関を示した。(4)ヒトRAGEミニ遺伝子とヒト由来HEK293T細胞を用いたRAGEmRNA選択的スプライシング解析系を確立し、各種ミニ遺伝子変異体を用いた解析により、可溶型RAGEmRNA産生を制御する配列を同定した。(5)hnRNP-Hが可溶型RAGEmRNA産生に促進的に作用することを明らかにした。(ii)VEGF受容体(Flt-1)mRNAの選択的3'端プロセシング(1)ヒト血管内皮細胞で産生されるFlt-1mRNAの3'端プロセシング/ポリA付加部位を3'-RACE法により決定した。(2)ヒトFlt-1のミニ遺伝子とヒト初代培養血管内皮細胞を用いたFlt-1mRNA選択的3'端プロセシング解析系を確立し、site-directed mutagenesisにより可溶型Flt-1mRNAの産生に必須な配列とそこに作用すると考えられる因子を同定した。<br />In this research, we studied the mechanisms of alternative pre-mRNA splicing/processing by which mRNAs for soluble RAGE and soluble VEGF receptor are produced, and their roles in the regulation of diabetic vascular complications and angiogenesis. Soluble RAGE has a protective activity against AGE-induced vascular cell injury and soluble VEGF receptor acts as a potent anti-angiogenic factor.(1) We isolated the marine equivalent of soluble RAGE by RT-PCR cloning. This study will provide an animal orthologue of soluble RAGE to clarify its roles in health and disease.(2) We investigated the expression of soluble RAGE protein in human organs and tissues by immunohistochemical analysis, and found that soluble RAGE was widely distributed in various organs and tissues including vascular endothelium, neurons, pancreatic β cells, macrophages/monocytes, bile ducts, salivary glands, digestive tracts, renal tubules, prostate, skin, and thyroid.(3) We developed enzyme-linked immunosorbent assay (ELISA) for human soluble RAGE and examined the association of plasma soluble RAGE level with atherosclerosis, and found that it inversely correlated with carotid or femoral atherosclerosis.(4) We established an assay system for RAGE alternative splicing using a human RAGE mini-gene and HEK293T cells. Transfection experiments with various mutant RAGE mini-genes identified cis-acting elements on RAGE pre-mRNA, which regulated the alternative splicing of soluble RAGE mRNA. We also found the involvement of hnRNP-H in the regulation of soluble RAGE mRNA production.(4) We established an assay system for alternative 3'-end processing of VEGF receptor-1 (Flt-1) mRNA using a human Flt-1 mini-gene and primary cultured human vascular endothelial cells, and identified a cis-acting element on Flt-1 pre-mRNA, which regulated the production of soluble Flt-1 mRNA.<br />研究課題/領域番号:17590241, 研究期間(年度):2005 – 2006<br />出典：「血管新生・糖尿病血管症罹患感受性を制御する選択的mRNAスプライシングの新機構」研究成果報告書 課題番号17590241（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-17590241/175902412006kenkyu_seika_hokoku_gaiyo/)を加工して作成
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| 6.
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米倉, 秀人 ; Yonekura, Hideto
概要:
金沢大学大学院・医学系研究科<br />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;r
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eceptor 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。<br />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.<br />研究課題/領域番号:13670113, 研究期間(年度):2001 – 2002<br />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
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