2001 年度実績報告書

腹膜透析における腹膜機能不全の病態解明及び新規治療法に向けての基盤技術の開発

研究課題

研究課題/領域番号	13307031
研究機関	東海大学
研究代表者	宮田敏男東海大学, 医学部, 助教授 (10222332)
研究分担者	黒川清東海大学, 医学部, 教授 (30167390)
キーワード	advanced glycation end products / AGE阻害剤 / カルボニルストレス / カルボニルトラップビーズ / グリオキサラーゼ / 腹膜透析 / トランスジェニックマウス
研究概要	腹膜透析の長期継続は腹膜の形態学的及び機能的変化の進行とともに困難となる。その原因の1つとして、腹膜透析患者腹腔内における、腹膜透析液および血液由来のカルボニルストレスの亢進が考えられる。カルボニルストレスの軽減化を目的として、カルボニル化合物の消去に関与するグリオキサラーゼ(GLO)とその補酵素であるグルタチオンを組み合わせたカルボニルストレス消去システム(グリオキサラーゼシステム)について検討を行った。GLO遺伝子を導入したGLO-l過剰発現培養細胞(Chinese hamster ovary細胞)を確立し、培養液中に添加したα-ジカルボニル化合物に対してカルボニルストレス抑制効果を確認した。また、GLO-lを過剰発現する動物モデル(トランスジェニックマウス)を作製したところ、各臓器においてGLO-lが高発現しており、各種臓器の細胞ライセートについても同様のカルボニルストレス抑制効果を確認した。これらのことから、GLO系の亢進によりカルボニルストレスの軽減化が期待できることが示唆された。また、カルボニル化合物トラップデバイスの開発に向けて、種々のリガンドをビーズに結合させたカルボニルトラップビーズを作製し、基礎的検討を行った。その結果、腹膜透析液中の種々のカルボニル化合物を効率良くトラップするビーズの開発に成功した。今後、さらにトラップ能の向上を目指して改良を図る。さらに、腎不全における合併症にカルボニルストレスが関与していることから、AGE(advanced glycation end products)阻害剤の有用性が期待される。我々は、副作用の少ないAGE阻害剤の開発を目指して各種の化合物について検討した。その結果、既存のAGE阻害剤より強いAGE抑制作用を有し、さらに、ヒドロキシラジカルやカーボンセンターラジカルの消去能を有しピリドキサールは捕捉しない化合物を見いだした。

研究成果

(29件)

すべてその他

すべて文献書誌 (29件)

[文献書誌] Takeda A, et al: "Neuronal and glial advanced glycation end poduct [N^ε-(carboxymethyl)lysine]in Alzheimer's disease brains"Acta Neuropathol. 101. 27-35 (2001)
[文献書誌] Hou FF, et al.: "β 2-Microglobulin modified with advanced glycation end products delays monocyte apoptosis and induces differenciation into macrophage-like cells"Kidney Int. 59. 990-1002 (2001)
[文献書誌] Miyata T, et al.: "Reactive carbonyl compound-related uremic toxicity(carbonyl stress)"Kidney Int. 59[Suppl 78]. 25-31 (2001)
[文献書誌] Ueda Y, et al.: "Does removal of glucose lower the carbonyl stress of glucose containing peritoneal dialysis?:effect of dwell time on icodextrin and amino acid PD fluids"Kidney Int. 58. 2518-2524 (2001)
[文献書誌] Yamada K, et al.: "Clusterin is up-regulated in glomerular mesangial cells in complement-mediated injury"Kidney Int. 59. 137-146 (2001)
[文献書誌] Miyata T, et al.: "Reactive carbonyl compounds as uremic toxins"Contrib Nephrol. 133. 71-80 (2001)
[文献書誌] Miyata T, et al.: "Advanced glycation and lipoxidation end products:reactive carbonyl compounds-related uraemic toxicity"Nephrol Dial Transplant. 16[Suppl 4]. 8-11 (2001)
[文献書誌] Nangaku M, et al.: "Cloning of rodent megsin revealed its up-regulation on mesangioproliferative nephritis"Kidney Int. 60. 641-652 (2001)
[文献書誌] Shao J, et al.: "Protective role of nitric oxide in a model of thrombotic microangiopathy in rats"J Am Soc Nephrol. 12. 2088-2097 (2001)
[文献書誌] Inagi R, et al.: "Specific tissue distribution of megsin,a novel serpin,in the glomerulus and its up-regulation in IgA nephropathy"Biochem Biophys Res Commun. 286. 1098-1106 (2001)
[文献書誌] Suzuki D, et al.: "Carbonyl Stress,Type-2 diabetic nephropathy in Japan from bench to bedside"Contributions to Nephrology. 13. 36-45 (2001)
[文献書誌] Combet S, et al.: "Chronic uremia induces permeability changes,increased nitric oxide synthase expression,and structural modifications in the peritoneum"J Am Soc Nephrol. 12. 2146-2157 (2001)
[文献書誌] Akhand AA, et al.: "Glyoxal and methylglyoxal induce aggergation and inactivation of ERK in human endothelial cells"Free Radic Biol Med. 15. 1228-1235 (2001)
[文献書誌] Miyata T, et al.: "Glyoxalase I deficiency is associated with an unusual level of advanced glycation end products in a hemodialysis patient"Kidney Int. 60. 2351-2359 (2001)
[文献書誌] Wada T, et al.: "Cloning and characterization of a novel subunit of protein serine/threonine phosphatase 4 from mesangial cells"J Am Soc Nephrol. 12. 2601-2608 (2001)
[文献書誌] Chen J, et al.: "Delayed branching of endothelial capillary cords in glycated collagens is mediated by the early induction of PAl-1"Am J Physiol. 281. 71-81 (2001)
[文献書誌] Morimoto K, et al.: "Cytoprotective role of heme oxygenase(HO)-1 in human kidney with various renal diseases"Kidney Int. 60. 1858-1866 (2001)
[文献書誌] Miyata T, et al.: "Advances in the biochemistry and pathophysiology of the peritoneal membrane:New therapeutic insights into more biocompatible peritoneal dialysis"Kidney Int. 61. 1858-1866 (2001)
[文献書誌] Kurokawa K, et al.: "Current issues and future perspectives of chronic renal failure"J Am Soc Nephrol. (in press).
[文献書誌] Miyata T, et al.: ""Carbonyl Stress"and long-term uremic complications"Advanced in Nephrology. (in press).
[文献書誌] Kurokawa K, et al.: "Future perspectives of chronic renal failure"Am J Kidney Dis. (in press).
[文献書誌] Ishibashi Y, et al.: "Glucose dialysate induces mitochondrial DNA damage in peritoneal mesothelial cells"Prit Dial Int. (in press).
[文献書誌] Asano M, et al.: "Renal tubular metabolism of protein-linked pentoisidine,an advanced glycation end product"Nephron. (in press).
[文献書誌] Miyata T, et al.: "Progressive mesangial expansion and hypercellularity in transgenic mice of mesangial cell-predominant serpin, megsin"J Clin Invest. (in press).
[文献書誌] Inagi R, et al.: "Efficient detoxification of carbonyl stress by the gloxalase system in peritoneal dialysis"Kidney Int. (in press).
[文献書誌] Miyata T, et al.: "Angiotensine II receptor antagonist and angiotensine converting enzyme(ACE)inhibitor scavenge oxidative radicals and lower the formation of advanced glycation end products"J Am Soc Nephrol. (in press).
[文献書誌] Miyata T, et al.: "Massry and Glassock's Text Book of Nephrology"Alterations in nonenzymatic biochemistry of carbohydrates and lipids in uremia. 1275-1278 (2001)
[文献書誌] Nangaku M, et al.: "Forum Issue of ARS"Relevance of oxidative and carbonyl stress in uremia(in press).
[文献書誌] Miyata T, et al.: "Nutritional Management of Renal Disease"Carbonyl stress in uremia(in press).

2001 年度 実績報告書

腹膜透析における腹膜機能不全の病態解明及び新規治療法に向けての基盤技術の開発

研究代表者

宮田 敏男 東海大学, 医学部, 助教授 (10222332)

研究成果

[文献書誌] Takeda A, et al: "Neuronal and glial advanced glycation end poduct [N^ε-(carboxymethyl)lysine]in Alzheimer's disease brains"Acta Neuropathol. 101. 27-35 (2001)

[文献書誌] Hou FF, et al.: "β 2-Microglobulin modified with advanced glycation end products delays monocyte apoptosis and induces differenciation into macrophage-like cells"Kidney Int. 59. 990-1002 (2001)

[文献書誌] Miyata T, et al.: "Reactive carbonyl compound-related uremic toxicity(carbonyl stress)"Kidney Int. 59[Suppl 78]. 25-31 (2001)

[文献書誌] Ueda Y, et al.: "Does removal of glucose lower the carbonyl stress of glucose containing peritoneal dialysis?:effect of dwell time on icodextrin and amino acid PD fluids"Kidney Int. 58. 2518-2524 (2001)

[文献書誌] Yamada K, et al.: "Clusterin is up-regulated in glomerular mesangial cells in complement-mediated injury"Kidney Int. 59. 137-146 (2001)

[文献書誌] Miyata T, et al.: "Reactive carbonyl compounds as uremic toxins"Contrib Nephrol. 133. 71-80 (2001)

[文献書誌] Miyata T, et al.: "Advanced glycation and lipoxidation end products:reactive carbonyl compounds-related uraemic toxicity"Nephrol Dial Transplant. 16[Suppl 4]. 8-11 (2001)

[文献書誌] Nangaku M, et al.: "Cloning of rodent megsin revealed its up-regulation on mesangioproliferative nephritis"Kidney Int. 60. 641-652 (2001)

[文献書誌] Shao J, et al.: "Protective role of nitric oxide in a model of thrombotic microangiopathy in rats"J Am Soc Nephrol. 12. 2088-2097 (2001)

[文献書誌] Inagi R, et al.: "Specific tissue distribution of megsin,a novel serpin,in the glomerulus and its up-regulation in IgA nephropathy"Biochem Biophys Res Commun. 286. 1098-1106 (2001)

[文献書誌] Suzuki D, et al.: "Carbonyl Stress,Type-2 diabetic nephropathy in Japan from bench to bedside"Contributions to Nephrology. 13. 36-45 (2001)

[文献書誌] Combet S, et al.: "Chronic uremia induces permeability changes,increased nitric oxide synthase expression,and structural modifications in the peritoneum"J Am Soc Nephrol. 12. 2146-2157 (2001)

[文献書誌] Akhand AA, et al.: "Glyoxal and methylglyoxal induce aggergation and inactivation of ERK in human endothelial cells"Free Radic Biol Med. 15. 1228-1235 (2001)

[文献書誌] Miyata T, et al.: "Glyoxalase I deficiency is associated with an unusual level of advanced glycation end products in a hemodialysis patient"Kidney Int. 60. 2351-2359 (2001)

[文献書誌] Wada T, et al.: "Cloning and characterization of a novel subunit of protein serine/threonine phosphatase 4 from mesangial cells"J Am Soc Nephrol. 12. 2601-2608 (2001)

[文献書誌] Chen J, et al.: "Delayed branching of endothelial capillary cords in glycated collagens is mediated by the early induction of PAl-1"Am J Physiol. 281. 71-81 (2001)

[文献書誌] Morimoto K, et al.: "Cytoprotective role of heme oxygenase(HO)-1 in human kidney with various renal diseases"Kidney Int. 60. 1858-1866 (2001)

[文献書誌] Miyata T, et al.: "Advances in the biochemistry and pathophysiology of the peritoneal membrane:New therapeutic insights into more biocompatible peritoneal dialysis"Kidney Int. 61. 1858-1866 (2001)

[文献書誌] Kurokawa K, et al.: "Current issues and future perspectives of chronic renal failure"J Am Soc Nephrol. (in press).

[文献書誌] Miyata T, et al.: ""Carbonyl Stress"and long-term uremic complications"Advanced in Nephrology. (in press).

[文献書誌] Kurokawa K, et al.: "Future perspectives of chronic renal failure"Am J Kidney Dis. (in press).

[文献書誌] Ishibashi Y, et al.: "Glucose dialysate induces mitochondrial DNA damage in peritoneal mesothelial cells"Prit Dial Int. (in press).

[文献書誌] Asano M, et al.: "Renal tubular metabolism of protein-linked pentoisidine,an advanced glycation end product"Nephron. (in press).

[文献書誌] Miyata T, et al.: "Progressive mesangial expansion and hypercellularity in transgenic mice of mesangial cell-predominant serpin, megsin"J Clin Invest. (in press).

[文献書誌] Inagi R, et al.: "Efficient detoxification of carbonyl stress by the gloxalase system in peritoneal dialysis"Kidney Int. (in press).

[文献書誌] Miyata T, et al.: "Angiotensine II receptor antagonist and angiotensine converting enzyme(ACE)inhibitor scavenge oxidative radicals and lower the formation of advanced glycation end products"J Am Soc Nephrol. (in press).

[文献書誌] Miyata T, et al.: "Massry and Glassock's Text Book of Nephrology"Alterations in nonenzymatic biochemistry of carbohydrates and lipids in uremia. 1275-1278 (2001)

[文献書誌] Nangaku M, et al.: "Forum Issue of ARS"Relevance of oxidative and carbonyl stress in uremia(in press).

[文献書誌] Miyata T, et al.: "Nutritional Management of Renal Disease"Carbonyl stress in uremia(in press).

2001 年度実績報告書

宮田敏男東海大学, 医学部, 助教授 (10222332)