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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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渡邉, 琢夫 ; Watanabe, Takuo
概要:
金沢大学医薬保健研究域医学系<br />1.細胞表面受容体のオリゴマー化モニタリング系の開発細胞膜受容体であるRAGE (receptor for advanced glycation endproducts)をモデルとし、2分子FRET法
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により受容体オリゴマー化をモニタリングする技術を確立した。これにより、受容体の蛍光タンパク融合組換え体を作製することなくFRETでオリゴマー化をモニタリングすることが可能となった。(1)RAGE細胞外ドメインに結合し、かつRAGEとリガンドとの結合を阻害しないモノクローナル抗体を作製し、FRETのドナーとアクセプターの対をなす2種の蛍光色素で標識した。(2)RAGE過剰発現細胞株の培養液中に上記の2種の蛍光標識抗体を加え、生細胞表面のRAGEを蛍光標識し、RAGEのオリゴマー化をFRETシグナルの変化を測定することによりモニタリングした。(3)その結果、リガンド刺激後20分をピークとするFRETシグナルの上昇が検出され、本技術の有効性が示された。2.1分子FRET法による細胞内シグナルモニタリングと受容体発現量の相関関係の解析細胞内シグナル強度のモニタリングと、受容体の発現量解析を同時に行うことにより、受容体発現量とシグナル強度の相関解析が可能な系を開発した。(1)NFκBの活性化によりβ-ラクタマーゼを発現するレポーター遺伝子を組み込んだ細胞株に、RAGE発現ベクターを導入した。(2)上記細胞にβ-ラクタマーゼによる分解で分子内FRETが消失する蛍光色素分子を取り込ませ、FRETシグナルによりNFκB活性化を検出すると同時に、蛍光抗体でRAGEを標識し発現量を測定した。(3)その結果、RAGE発現量が中程度の細胞において最も強くNFκBが活性化されており、発現量が過剰な細胞ではむしろ活性化の程度が低いことが明らかとなった。<br />研究課題/領域番号:18038017, 研究期間(年度):2006<br />出典：「細胞膜受容体の分子挙動と細胞応答の統合的測定技術の開発」研究成果報告書 課題番号18038017（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/grant/KAKENHI-PROJECT-18038017/)を加工して作成
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| 6.
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棟居, 聖一 ; Munesue, Seiichi
概要:
金沢大学医薬保健研究域医学系<br />マルチリガンド受容体として知られるRAGE（receptor for advanced glycation end-products）は種々のリガンドと結合して細胞内シグナルを誘導し、その結果、糖尿病
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血管障害、がん、炎症、アルツハイマー病等の病態を悪化させる。それゆえ、RAGEシグナルを阻害することは、RAGE関連疾患の予防・治療にとって重要である。研究代表者らはRAGEシグナル阻害成分が含まれる醤油由来の低分子画分を分離・精製し、その成分を明らかにした。さらに、RAGEの多量体形成に及ぼす細胞外領域を明らかにするためリガンド結合部位等を欠損させた組換えRAGEを作製しCOS7細胞に導入した。<br />Receptor for advanced glycation end products (RAGE) is a pattern recognition receptor, which has been implicated in the pathogenesis of diabetic complications, inflammation, Alzheimer's disease, and cancer. Therefore it is important for RAGE relation diseases to inhibit RAGE signaling. In this study, we isolated and identified RAGE signaling inhibitory components derived from Japanese soy sauce low molecular fraction. Furthermore cos7 cells were transfected with a plasmid containing full length RAGE cDNA and V1, C1, C2 domain-deleted RAGE cDNAs to clear the essential domain for RAGE multimerization.<br />研究課題/領域番号:26450152, 研究期間(年度):2014-04-01 - 2017-03-31
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| 7.
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山本, 靖彦 ; Yamamoto, Yasuhiko
概要:
金沢大学医薬保健研究域医学系<br />糖尿病血管障害の新規予防・治療法の開発を目指した。標的とするのは、パターン認識受容体の一つで糖尿病血管合併症に関わる膜型受容体RAGE（receptor for advanced glycation
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end-products）であり、その受容体のectodomain sheddingの誘発によりシグナル伝達型RAGEを切断し、デコイ受容体として働く可溶型RAGE（soluble RAGE, sRAGE）を生み出す手法に焦点を当てた。薬剤・化合物ライブラリースクリーニングと検証実験から、複数の候補化合物を同定することに成功し、今後は糖尿病血管障害の新規治療法として臨床への応用が期待された。<br />Receptor for advanced glycation end-products (RAGE) is considered linked to the onset and progression of diabetic vascular complications and atherosclerosis. By focusing on target therapies against RAGE, one potentially useful strategy is the conversion of the membrane-bound form of RAGE (mRAGE) to soluble isoform (sRAGE). The ectodomain shedding can increase the sRAGE level and concomitantly decrease mRAGE expression, potentially leading to the prevention and the attenuation of the diabetic vascular diseases. In this study, we screened drug and chemical libraries and identified useful candidates to mediate the ectodomain shedding of RAGE. Our finding will provide promising drugs for treating diabetic patients.<br />研究課題/領域番号:24590375, 研究期間(年度):2012-04-01 - 2015-03-31
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| 8.
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喜多, 大輔 ; Kita, Daisuke
概要:
金沢大学附属病院<br />本研究は、水頭症発生とRAGEの関与につき探求することを目的とした。内因性分泌型esRAGE遺伝子導入マウスにおける水頭症浸透率は3%程であった。ヒト特発性正常圧水頭症でRAGEの関与は見いだせなかった。ヒトでの
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長期に渡る水頭症患者において脳実質破壊の度合いが脳室の形状に相関があり、RAGE発現との相関が示唆された。本研究とともに、ヒトにおける脳室拡大の継時的変化に関する研究、長期にわたる水頭症患者における髄液吸収能の保持に関する論文、さらに脳室拡大と脳室形状に関する国際学会発表を行った。<br />The main aim of this study was to investigate whether there is co-relation between RAGE and hydrocephalus. In endosecratory RAGE (esRAGE) transgenic mice, we identified about 3% of penetration rate of hydrocephalus, while in human hydrocephalus patients, we couldn’t find such relationship because of difficulty in measuring expression levels of esRAGE from human cerebrospinal fluid. Next, we focused on expression of esRAGE in brain and the way of enlargement of ventricular system. We found that esRAGE was expressed abundantly in human choroid plexus, though there was no relationship between the expression of RAGE and development of hydrocephalus in human. Besides RAGE study, we published two papers on developmental process of hydrocephalus in a young adult, and retention of CSF absorptive capacity in long-standing hydrocephalus patients. We presented a paper on relationship between white mater damage and hydrocephalus in the elderly in an international meeting on hydrocephalus.<br />研究課題/領域番号:25670620, 研究期間(年度):2013-04-01 – 2016-03-31
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| 9.
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山本, 博 ; Yamamoto, Hiroshi
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金沢大学医薬保健研究域医学系<br />2型糖尿病では膵ランゲルハンス島β細胞からのインスリン分泌が徐々に低下し膵β細胞疲弊が生じる。このメカニズムを解明するため、高血糖による糖毒性物質advanced glycation end-prod
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ucts (AGE)とその細胞膜受容体receptor for AGE (RAGE)に着目し、レプチンシグナル不全のdb/dbマウスを使って検討した。また、マウス膵β細胞由来MIN6細胞を用いて糖脂肪毒性の影響を調べた。レプチン受容体シグナルの遮断と、遊離脂肪酸の暴露によって膵β細胞膜上のRAGE発現誘導が生じ、さらにAGE刺激によって膵β細胞はアポトーシス、インスリン分泌不全に陥ると結論された。<br />Glucolipotoxicity, which is exerted by free fatty acids (FFA) and prolonged hyperglycemia, is implicated in pancreatic β-cell failure in diabetes. We examined whether advanced glycation end-products (AGE) and RAGE contribute to β-cell failure in a type 2 diabetes mouse model. Pretreatment of FFA combined with a leptin antagonist induced RAGE expression, AGE-elicited apoptosis, and impaired glucose-stimulated insulin secretion by AGE in MIN6 cells. FFA elevation with concomitant AGE formation during prolonged hyperglycemia could cause β-cell damage through insufficient leptin action and subsequent RAGE induction in type 2 diabetes.<br />研究課題/領域番号:25461335, 研究期間(年度):2013-04-01 – 2016-03-31
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| 10.
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山本, 博 ; Yamamoto, Hiroshi
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1)マウスマクロファージの培養系を用いて,リガンド添加によるRAGEシグナルがcAMP 依存性シグナル伝達経路によって抑制されることを明らかにした。 (2)cAMP依存性シグナルは,MMP9を活性化し膜結合型RAGEのシェディングを促進する
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ことにより,膜結合型RAGEを減少させ可溶型RAGEを増加させることを明らかにした。 (3)cAMP依存性シグナルがRAGEリガンド-RAGE系シグナルを抑制するメカニズムとして,cAMP依存性シグナルによる膜結合型RAGEのシェディング促進が,シグナル伝達に関わる膜結合型RAGE を減少させる一方,デコイ受容体として働く可溶型RAGE を増加させることが考えられた。<br />(1) We found that ligand-dependent RAGE signal was suppressed by cAMP-dependent signaling pathway, using mouse macrophage culture system.(2) We showed that cAMP-dependent signal caused activation of MMP9 that accelerated shedding of membrane-bound form RAGE, which resulted in decrease of membrane-bound form RAGE and increase of soluble form RAGE.(3) The mechanism of the suppression of ligand-dependent RAGE signal by cAMP-dependent signal was supposed that the acceleration of shedding of membrane-bound form RAGE via cAMP-dependent signal resulted in decrease of membrane-bound form RAGE functioning signal transducer and increase of soluble form RAGE functioning decoy receptor.<br />研究課題/領域番号:23659430, 研究期間(年度):2011–2012
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