1999 Fiscal Year Annual Research Report

糖尿病合併症のおけるAGE受容体の意義

Research Project

Project/Area Number	11557081
Research Category	Grant-in-Aid for Scientific Research (B)
Research Institution	Kumamoto University
Principal Investigator	堀内正公熊本大学, 医学部, 教授 (10117377)
Co-Investigator(Kenkyū-buntansha)	小池博之三共株式会社, 第一生物研究所, 所長山田信博筑波大学, 臨床医学系, 教授 (40200729)
Keywords	糖尿病合併症 / メイラード反応後期生成物 / AGE / AGE受容体 / スカベンジャー受容体 / RAGE / Galectin-3 / ノックアウトマウス
Research Abstract	蛋白はグルコースによって非酵素的に糖化を受け、後期反応生成物(AGE: Advanced Glycation Endproducts)を形成する。AGEは糖尿病合併症の発症機構の一つとして注目されており、特に、AGE蛋白をリガンドとして認識し、種々の細胞現象を惹起するAGE受容体の意義の解明は重要である。現在、AGE受容体としてMSR-A、Galectin-3及びRAGEの3つの受容体が提唱されている。本年度は主としてGalectin-3とRAGEに関して解析を進めた。ヒトGalectin-3を真核細胞(CHO細胞)に過剰発現させた細胞を樹立した。この細胞はAGE蛋白を受容体依存的に取り込み分解した。又、アセチルLDLや酸化LDLに対しても同様の挙動を示した。リガンド競合実験の結果はこれらのリガンドが同一の受容体を介して取り込まれていることを示しており、Galectin-3がAGE受容体として機能していることが示唆された。我々は米国サウスカロライナ大学医学部ナチガル教授との共同実験でGalectin-3ノックアウトマウスの作製に成功した。これらのマウスの腹腔マクロファージを用いた予備実験の結果は、当初の予想に反して、AGE蛋白の取り込みは野生型のそれと比較して、減少することはなく、有意な増加傾向を示した。Galectin-3はMac-2結合蛋白を介して細胞膜と結合しており、現在、Mac-2結合蛋白の発現、及び(我々が既に証明しているAGE受容体である)MSR-Aの発現を特異抗体を用いて細胞レベルで解析している。又、MSR-AとGalectin-3の両者を欠損するノックアウトマウスの作製にも着手した。RAGEに関しては、ヒトRAGEを高発現するCHO細胞を作製し、現在、AGE蛋白との結合を解析している。

Research Products
(15 results)

All Other

All Publications (15 results)

[Publications] Sakata N et al.: "Increased advanced glycation end products in atheroscleroric lesions of patients with endstage renal disease"Atherosclerosis. 142. 67-77 (1999)
[Publications] Abiko,T et al.: "Relationship between autofluorescence and advanced glycation end products in diabetic lenses."Exp. Eye Res.. 68. 361-366 (1999)
[Publications] Shibata N et al.: "Advanced glycation endproducts are deposited in neuronal hyaline inclusions: a study on familial amyotrophic lateral sclerosis with superoxide dismutase-1 mutation"Acta Neuropathol.. 97. 240-246 (1999)
[Publications] Kato S et al.: "Astrocytic hyaline inclusions contain advanced glycation endproducts in familial amyotrophiclateral sclerosis with superoxide dismutase 1 gene mutation: imunohisto-chemical and immunoelectron microscopical analyses."Acta Neuropathol.. 97. 260-266 (1999)
[Publications] Ando K et al.: "Membrane proteins of human erythrocytes are modified by advanced glycation end products (AGEs) during aging in the circulation."Biochem. Biophys. Res. Commun.. 258. 123-127 (1999)
[Publications] Uesugi N et al.: "Glycoxidative modification promotes renal AA amyloid"Deposition. Nephrol. Dial. Transplant.. 15. 355-365 (1999)
[Publications] Tajima K et al.: "Hereditary ceruloplasminemia deficiency increases advanced glycation end products in the brain"Neurology. 53. 619-622 (1999)
[Publications] Sugimoto H et al.: "Advanced glycation end products-cytokine-nitric oxide sequence pathway in the development of diabetic nephropathy: aminoguanidine ameliorates the overexpression of tumor necrosis factor-alpha and inducible nitric oxide synthase in diabetic rat glomeruli"Diabetologia. 42. 878-886 (1999)
[Publications] Honda K et al.: "Accumualtion of advanced glycation end products in the peritoneal vasculature of continuous ambulatory peritoneal dialysis patients with low ultra-filtration"Nephrol. Dial. Transplant. 14. 1541-1549 (1999)
[Publications] Sasaki T et al.: "The effect of interleukin (IL)-4 and IL-10 on macrophage growth-stimulating activities of oxidized low density lipoprotein (IDL), accetylated IDL and macrophage colony stimulating factor: the actrivity of oxidized IDL is refractory to the inhibitory cytokines"Pharm. Bull.. 22. 1002-1006 (1999)
[Publications] Sasaki T et al.: "Induction of GM-CSF production of macrophages by advanced glycation end products of the Maillard reaction"Biosci. Biotechnol. Biochem.. 63. 2011-2013 (1999)
[Publications] Shibayama R et al.: "Autoantibody Against Nε-(carboxymehtyl)lysine: an advanced glycation end product of the Maillard reaction"Diabetes. 48. 1842-1849 (1999)
[Publications] Iwashima Y et al.: "Advanced glycation end product-induced peroxisome proliferator-activated receptor gamma gene expression in the cultured mesangial cells"Biochem. Biophys Res. Commun.. 264. 441-448 (1999)
[Publications] Kaji Y et al.: "Advanced glycation en products in diabetic corneas"Invest. Ophthalmol. Vis. Sci.. 41. 362-368 (1999)
[Publications] Imanaga Y et al.: "In vivo and in vitro evidences for glycoxidation of low density lipoprotein in human atherosclerotic plaques"Atherosclerosis. (in press).

1999 Fiscal Year Annual Research Report

糖尿病合併症のおけるAGE受容体の意義

Principal Investigator

堀内 正公 熊本大学, 医学部, 教授 (10117377)

Research Products

[Publications] Sakata N et al.: "Increased advanced glycation end products in atheroscleroric lesions of patients with endstage renal disease"Atherosclerosis. 142. 67-77 (1999)

[Publications] Abiko,T et al.: "Relationship between autofluorescence and advanced glycation end products in diabetic lenses."Exp. Eye Res.. 68. 361-366 (1999)

[Publications] Shibata N et al.: "Advanced glycation endproducts are deposited in neuronal hyaline inclusions: a study on familial amyotrophic lateral sclerosis with superoxide dismutase-1 mutation"Acta Neuropathol.. 97. 240-246 (1999)

[Publications] Kato S et al.: "Astrocytic hyaline inclusions contain advanced glycation endproducts in familial amyotrophiclateral sclerosis with superoxide dismutase 1 gene mutation: imunohisto-chemical and immunoelectron microscopical analyses."Acta Neuropathol.. 97. 260-266 (1999)

[Publications] Ando K et al.: "Membrane proteins of human erythrocytes are modified by advanced glycation end products (AGEs) during aging in the circulation."Biochem. Biophys. Res. Commun.. 258. 123-127 (1999)

[Publications] Uesugi N et al.: "Glycoxidative modification promotes renal AA amyloid"Deposition. Nephrol. Dial. Transplant.. 15. 355-365 (1999)

[Publications] Tajima K et al.: "Hereditary ceruloplasminemia deficiency increases advanced glycation end products in the brain"Neurology. 53. 619-622 (1999)

[Publications] Honda K et al.: "Accumualtion of advanced glycation end products in the peritoneal vasculature of continuous ambulatory peritoneal dialysis patients with low ultra-filtration"Nephrol. Dial. Transplant. 14. 1541-1549 (1999)

[Publications] Sasaki T et al.: "Induction of GM-CSF production of macrophages by advanced glycation end products of the Maillard reaction"Biosci. Biotechnol. Biochem.. 63. 2011-2013 (1999)

[Publications] Shibayama R et al.: "Autoantibody Against Nε-(carboxymehtyl)lysine: an advanced glycation end product of the Maillard reaction"Diabetes. 48. 1842-1849 (1999)

[Publications] Iwashima Y et al.: "Advanced glycation end product-induced peroxisome proliferator-activated receptor gamma gene expression in the cultured mesangial cells"Biochem. Biophys Res. Commun.. 264. 441-448 (1999)

[Publications] Kaji Y et al.: "Advanced glycation en products in diabetic corneas"Invest. Ophthalmol. Vis. Sci.. 41. 362-368 (1999)

[Publications] Imanaga Y et al.: "In vivo and in vitro evidences for glycoxidation of low density lipoprotein in human atherosclerotic plaques"Atherosclerosis. (in press).

堀内正公熊本大学, 医学部, 教授 (10117377)