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論文
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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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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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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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論文
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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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