主要AGE構造体の同定とその臨床への応用

• Project/Area Number: 16790511
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Metabolomics
• Research Institution: Kumamoto University
• Principal Investigator: 永井 竜児 熊本大学, 大学院医学薬学研究部, 助手 (20315295)
• Project Period (FY): 2004 – 2005
• Project Status: Completed (Fiscal Year 2005)
• Budget Amount: ¥3,500,000 (Direct Cost: ¥3,500,000); Fiscal Year 2005: ¥1,400,000 (Direct Cost: ¥1,400,000); Fiscal Year 2004: ¥2,100,000 (Direct Cost: ¥2,100,000)
• Keywords: メイラード反応 / AGE / グリケーション / 翻訳後修飾 / 糖尿病合併症 / 動脈硬化症

Research Abstract

生体には様々な翻訳後修飾の機構が存在するが、メイラード反応は特に糖尿病合併症、動脈硬化症といった加齢に伴って発症頻度が増加する病態との関与が強く指摘されている。申請者はメイラード反応後期生成物であるAdvanced glycation end products(AGE)の生成メカニズムを分子レベルで解析している。平成17年度の研究成果より、(1)我々が発見したglycolaldehyde由来新規AGE構造体であるGA-pyridineが糖尿病性腎症の糸球体に蓄積し、さらにその蓄積度は病態の進行に伴って促進していることから、腎症の進展にはglycolaldehydeによる蛋白の修飾が関与していることが明らかとなった。(2)腎症モデルラットにおいて、腎症の進展に伴って糸球体にAGE構造体の一つであるPentosidineが蓄積することが明らかとなり、GA-pyridineと同様、腎症の進展にはAGEによる蛋白の翻訳後修飾が関与している可能性が示唆された。(3)システインとフマル酸とのadductである(2-succinyl)cysteine(2SC)を同定した。本構造がヒト血清アルブミン等に存在することから、生体でクレブスサイクルによる蛋白の翻訳後修飾が進行していることを明らかにした。(4)肺胞II型細胞株として知られるA549細胞に発現するAGE受容体を解析した結果、本細胞には以前に我々がAGE受容体として報告したscavenger receptor familyとは異なる新規のAGE受容体が発現していることが明らかとなった。

Research Products

• [Journal Article] Association of advanced glycation end products to A549 cells, a human pulmonary epithelial cell line, is mediated by a receptor distinct from scavenger receptor family ant RAGE (2006)
  • Author(s): Nakano N et al.
  • Journal Title: J.Biochem. (In press)
• [Journal Article] S-(2-succinyl)cysteine : a novel chemical modification of tissue proteins by a Krebs cycle intermediate (2006)
  • Author(s): Alderson NL et al.
  • Journal Title: ACS Chemical Biology (In press)
• [Journal Article] Advanced Oxidation Protein Products Accelerate Atherosclerosis Through Promoting Oxidative Stress and Inflammation (2006)
  • Author(s): Liu SX et al.
  • Journal Title: Arterioscler Thromb Vasc Biol (In press)
• [Journal Article] Advanced glycation end product is implicated in amyloid-related kidney complications. (2005)
  • Author(s): Matsunaga N et al.
  • Journal Title: Scand.J.Clin.Lab.Invest 65 Pages: 263-271
• [Journal Article] Effect of glucose concentration on formation of AGEs in erythrocytes in vitro (2005)
  • Author(s): Nagai R et al.
  • Journal Title: Ann.NY Acad.Sci 1043 Pages: 146-150
• [Journal Article] Renal Accumulation of Pentosidine in Non-Diabetic Proteinuria-Induced Renal Damage in Rats (2005)
  • Author(s): Waanders F et al.
  • Journal Title: Kid.Dial.Trans. 20 Pages: 2060-2070
• [Journal Article] Mesangial Accumulation of GA-pyridine a Novel Glycolaldehyde-derived AGE, in Human Renal Disease (2005)
  • Author(s): Greven WL et al.
  • Journal Title: Kid.Int. 68 Pages: 595-602
• [Journal Article] Migration of keratinocytes is impaired on glycated collagen I. (2005)
  • Author(s): Morita K et al.
  • Journal Title: Wound Repair Regen 13 Pages: 93-101
• [Journal Article] メイラード反応 (2005)
  • Author(s): 永井竜児ら
  • Journal Title: 日本糖尿病学会雑誌 48 Pages: 403-405
• [Journal Article] マクロファージ (2005)
  • Author(s): 永井竜児ら
  • Journal Title: 酸化ストレスナビゲーター Pages: 64-65
• [Journal Article] Migration of keratinocytes is impaired on glycated collagen I (2005)
  • Author(s): Morita K et al.
  • Journal Title: Wound Repair Regen 13 Pages: 93-101
• [Journal Article] Accumultion of Advanced Glycation End Products in Age-dependent Disorders (2004)
  • Author(s): Nagai R et al.
  • Journal Title: Med.Hypotheses Res 1 Pages: 159-168
• [Journal Article] Conventional antibody against N^ε-(Carboxymethyl)lysine (CML) shows cross-reaction to N^ε-(Carboxyethyl)lysine (CEL) (2004)
  • Author(s): Koito W et al.
  • Journal Title: J Biochem 136 Pages: 831-837
• [Journal Article] Advanced glycation end products-modified proteins and oxidized LDL mediate down-regulation of leptin in mouse adipocytes via CD36 (2004)
  • Author(s): Unno Y et al.
  • Journal Title: Biochem.Biophys.Res.Commun 325 Pages: 151-156
• [Journal Article] Overproduction of N^ε-(Carboxymethyl)lysine-induced neovascularization in cultured choroidal explant of streptozotocin-diabetic Rat (2004)
  • Author(s): Kobayashi S et al.
  • Journal Title: Biol Pharm Bull 27 Pages: 1565-1571
• [Journal Article] N^ε-(carboxymethyl)lysine and 3-DG-imidazolone are major AGE structures in protein modification by 3-deoxyglucosone. (2004)
  • Author(s): Jono T
  • Journal Title: J Biochems 136 Pages: 351-358
• [Journal Article] N^ε-(Carboxymethyl)lysine Proliferated CD34(+) cells from rat choroidal explant in culture. (2004)
  • Author(s): Kobayashi S et al.
  • Journal Title: Biil Pharm Bull. 27 Pages: 1382-1387
• [Journal Article] Chemical modification of muscle protein in diabetes (2004)
  • Author(s): Alt N et al.
  • Journal Title: Arch Biochem Biophys 425 Pages: 200-206
• [Journal Article] Vascular change of hippocampal capillary is associated with vascular change of retinal capillary in aging (2004)
  • Author(s): Hagino N et al.
  • Journal Title: Brain Res Bull 62 Pages: 537-547
• [Journal Article] Increased production of urea hydrogen peroxide from Maillard reaction and a UHP-Fenton pathway related to glycoxidation damage in chronic renal failure (2004)
  • Author(s): Moh A
  • Journal Title: J Am Soc Nephrol 4 Pages: 1077-1085
• [Journal Article] Calcification of the Medial Layer of the Internal Thoracic Artery in Diabetic Patients : Relevance of Glycoxidation (2004)
  • Author(s): Sakata N et al.
  • Journal Title: J Vasc Res 40 Pages: 567-574
• [Journal Article] グリケーションと老化 (2004)
  • Author(s): 永井竜児
  • Journal Title: 日本アフェレシス学会雑誌 23 Pages: 151-157
• [Book] 糖尿病・代謝症候群の合併症 (2004)
  • Author(s): 永井竜児ら