2000 年度実績報告書

糖尿病合併症におけるAGE受容体の意義

研究課題

研究課題/領域番号	11557081
研究機関	熊本大学
研究代表者	堀内正公熊本大学, 医学部, 教授 (10117377)
研究分担者	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)
キーワード	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
研究概要	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RAGE、Galectin-3、及びスカベンジャー受容体ファミリーの一員であるSR-Aの3つの受容体が提唱されている。平成12年度は以下の結果を得た。ヒトGalectin-3をCHO細胞に過剰発現させた細胞はAGE蛋白を受容体依存的に活発に取り込み分解(endocytosis)した。取り込み経路はアセチルLDLや酸化LDLと酷似したものであると考えられた。このin vitro実験からは、Galectin-3がAGE受容体として機能していることが示唆されたが、Galecin-3遺伝子欠損マウスの腹腔マクロファージによるAGE蛋白の取り込み・分解活性は野生型のそれと著変を認めなかった。現在、遺伝子欠損マウスの実験を繰り返して、in vivoでのGalectin-3の機能を明確している。RAGEを高く発現しているヒト肺胞II型細胞であるA549細胞に対して、AGE蛋白は容量依存的な飽和曲線で結合した。又、AGEリガンドの本細胞への結合はNFkBの誘導を起こした。Class Aスカベンジャー受容体であるSR-Aに加えて、Class Bスカベンジャー受容体に属するCD36およびSR-BIを高発現したCHO細胞がAGE蛋白を効率的に取り込むことから、CD36およびSR-BIもAGE受容体として機能している可能性が示唆された。

研究成果
(21件)

すべてその他

すべて文献書誌 (21件)

[文献書誌] Ohgami N et al.,: "Scavenger receptor classB type I-mediated reverse cholesterol transport is inhibited by advanced glycation end product"J.Biol.Chem.. (In press). (2001)
[文献書誌] Meng J et al.,: "Tissue carboxymethyllysine in diabetic and non-diabetic patients with chronic renal failure : relevance to glycoxidation damage."Nephron.. (In press). (2000)
[文献書誌] Kyu-Kyu M et al.,: "Induction of acyl-coenzyme A : cholesterol acyltransferase-1 by 1,25-dihydroxyvitamin D3 or 9-cis-retinoic acid in undifferentiated THP-1 cells"J.Lipid Res.. (In press). (2001)
[文献書誌] Ohgami N et al.,: "CD36, a member of class B scavenger receptor family, as a receptor for advanced glycation end products (AGE)."J.Biol.Chem.. 276. 3195-3202 (2001)
[文献書誌] Sakata N et al.,: "Possible involvement of altered RGD sequence in reduced adhesive and spreading activities of advanced glycation end product-modified fibronectin to vascular smooth muscle cells."Connective Tissue Research. (In press). (2000)
[文献書誌] Amano S et al.,: "Advanced glycation end products in human optic nerve head"Br J.Ophthalmol.. 85. 52-55 (2001)
[文献書誌] Iwashima Y et al.,: "Advanced glycation end products-induced gene expression of scaven receptors in cultured human monocyte-derived macrophages."Biochem.Biophys.Res.Commun.. 277. 368-380 (2000)
[文献書誌] Matsumoto K et al.,: "Endocytic uptake of advanced glycation end products by mouse liver sinusoidal endothelial cells is mediated by a scavenger receptor distinct from the macrophage scavenger receptor-A (MSR-A)."Biochem.J.. 352. 233-240 (2000)
[文献書誌] Hamada Y et al.,: "Epalrestat, an aldose reductase inhibitor, reduces the levels of Ne-(carboxymethy) lysine protein adducts and their precursors in erythrocytes from diabetic patients"Diabetes Care. 23. 1539-1544 (2000)
[文献書誌] Ohgami N et al.,: "Glibenclamide acts as an inhibitor of acyl-CoA : cholesterol acyltransferase (ACAT) enzyme"Biochem.Biophys.Res.Commun.. 277. 417-422 (2000)
[文献書誌] Nagai R et al.,: "Glycolaldehyde, a reactive intermediate for advanced glycation endproducts, plays an important role in the generation of an active ligand for the macrophage scavenger receptor."Diabetes. 49. 1714-1723 (2000)
[文献書誌] Miyazaki A et al.,: "Granulocyte macrophage colony-stimulating factor plays a priming role in murine macroph growth induced by oxidized low density lipoprotein."Ann.N.Y.Acad.Sci.. 902. 342-342 (2000)
[文献書誌] Abiko A et al.,: "Increased levels of advanced glycosylation end products in the kidney and liver from spontaneously diabetic Chinese hamsters determined by immunochemical assay."Metabolism.. 49. 567-573 (2000)
[文献書誌] Nyhlin N et al.,: "Advanced glycation end product in familial amyloidotic polyneuropathy(FAP)."J.Int.Med.. 247. 485-492 (2000)
[文献書誌] Kato S et al.,: "Advanced glycation endproduct-modified superoxide dismutase-1 (SOD1)-positive inclusions are common to familial amyotrophic lateral Sclerosis patients with SOD1 gene mutations and transgenic mice expressing human SOD1 with G85R mutation."Neuropathol. 100. 490-505 (2000)
[文献書誌] Shibata N et al.,: "Nonoxidative protein glycation is implicated in familial amyotrophic lateral sclerosis with superoxide dismutase-1 mutation"Acta Neuropathol. 100. 275-284 (2000)
[文献書誌] Imanaga Y et al.,: "In vivo and in vitro evidence for the glycoxidation of low density lipoprotein in human atherosclerotic plaques."Atherosclerosis . 150. 343-355 (2000)
[文献書誌] Uesugi N et al.,: "Glycoxidative modification of AA amyloid deposits in renal tissue."Nephrol.Dial.Transplant.. 15. 355-365 (2000)
[文献書誌] Biwa T et al.,: "Sites of action of protein kinase C and phosphatidylinositol 3-kinase are distinct from oxidized low density lipoprotein-induced macrophage proliferation."J.Biol.Chem.. 275. 5810-5816 (2000)
[文献書誌] Sakashita N et al.,: "Localization of human acyl-Coenzyme A : cholesterol acyltransferase-1 (ACAT-1) in macrophages and in various tissues."Am.J.Pathol.. 156. 227-236 (2000)
[文献書誌] Kaji Y et al.,: "Advanced glycation end products in diabetic corneas."Invest.Ophthalmol.Vis.Sci.. 41. 362-368 (2000)

2000 年度 実績報告書

糖尿病合併症におけるAGE受容体の意義

研究代表者

堀内 正公 熊本大学, 医学部, 教授 (10117377)

研究成果

[文献書誌] Ohgami N et al.,: "Scavenger receptor classB type I-mediated reverse cholesterol transport is inhibited by advanced glycation end product"J.Biol.Chem.. (In press). (2001)

[文献書誌] Meng J et al.,: "Tissue carboxymethyllysine in diabetic and non-diabetic patients with chronic renal failure : relevance to glycoxidation damage."Nephron.. (In press). (2000)

[文献書誌] Kyu-Kyu M et al.,: "Induction of acyl-coenzyme A : cholesterol acyltransferase-1 by 1,25-dihydroxyvitamin D3 or 9-cis-retinoic acid in undifferentiated THP-1 cells"J.Lipid Res.. (In press). (2001)

[文献書誌] Ohgami N et al.,: "CD36, a member of class B scavenger receptor family, as a receptor for advanced glycation end products (AGE)."J.Biol.Chem.. 276. 3195-3202 (2001)

[文献書誌] Sakata N et al.,: "Possible involvement of altered RGD sequence in reduced adhesive and spreading activities of advanced glycation end product-modified fibronectin to vascular smooth muscle cells."Connective Tissue Research. (In press). (2000)

[文献書誌] Amano S et al.,: "Advanced glycation end products in human optic nerve head"Br J.Ophthalmol.. 85. 52-55 (2001)

[文献書誌] Iwashima Y et al.,: "Advanced glycation end products-induced gene expression of scaven receptors in cultured human monocyte-derived macrophages."Biochem.Biophys.Res.Commun.. 277. 368-380 (2000)

[文献書誌] Matsumoto K et al.,: "Endocytic uptake of advanced glycation end products by mouse liver sinusoidal endothelial cells is mediated by a scavenger receptor distinct from the macrophage scavenger receptor-A (MSR-A)."Biochem.J.. 352. 233-240 (2000)

[文献書誌] Hamada Y et al.,: "Epalrestat, an aldose reductase inhibitor, reduces the levels of Ne-(carboxymethy) lysine protein adducts and their precursors in erythrocytes from diabetic patients"Diabetes Care. 23. 1539-1544 (2000)

[文献書誌] Ohgami N et al.,: "Glibenclamide acts as an inhibitor of acyl-CoA : cholesterol acyltransferase (ACAT) enzyme"Biochem.Biophys.Res.Commun.. 277. 417-422 (2000)

[文献書誌] Nagai R et al.,: "Glycolaldehyde, a reactive intermediate for advanced glycation endproducts, plays an important role in the generation of an active ligand for the macrophage scavenger receptor."Diabetes. 49. 1714-1723 (2000)

[文献書誌] Miyazaki A et al.,: "Granulocyte macrophage colony-stimulating factor plays a priming role in murine macroph growth induced by oxidized low density lipoprotein."Ann.N.Y.Acad.Sci.. 902. 342-342 (2000)

[文献書誌] Abiko A et al.,: "Increased levels of advanced glycosylation end products in the kidney and liver from spontaneously diabetic Chinese hamsters determined by immunochemical assay."Metabolism.. 49. 567-573 (2000)

[文献書誌] Nyhlin N et al.,: "Advanced glycation end product in familial amyloidotic polyneuropathy(FAP)."J.Int.Med.. 247. 485-492 (2000)

[文献書誌] Shibata N et al.,: "Nonoxidative protein glycation is implicated in familial amyotrophic lateral sclerosis with superoxide dismutase-1 mutation"Acta Neuropathol. 100. 275-284 (2000)

[文献書誌] Imanaga Y et al.,: "In vivo and in vitro evidence for the glycoxidation of low density lipoprotein in human atherosclerotic plaques."Atherosclerosis . 150. 343-355 (2000)

[文献書誌] Uesugi N et al.,: "Glycoxidative modification of AA amyloid deposits in renal tissue."Nephrol.Dial.Transplant.. 15. 355-365 (2000)

[文献書誌] Biwa T et al.,: "Sites of action of protein kinase C and phosphatidylinositol 3-kinase are distinct from oxidized low density lipoprotein-induced macrophage proliferation."J.Biol.Chem.. 275. 5810-5816 (2000)

[文献書誌] Sakashita N et al.,: "Localization of human acyl-Coenzyme A : cholesterol acyltransferase-1 (ACAT-1) in macrophages and in various tissues."Am.J.Pathol.. 156. 227-236 (2000)

[文献書誌] Kaji Y et al.,: "Advanced glycation end products in diabetic corneas."Invest.Ophthalmol.Vis.Sci.. 41. 362-368 (2000)

2000 年度実績報告書

堀内正公熊本大学, 医学部, 教授 (10117377)