2001 Fiscal Year Annual Research Report

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

Research Project

Project/Area Number	13307031
Research Institution	Tokai University
Principal Investigator	宮田敏男東海大学, 医学部, 助教授 (10222332)
Co-Investigator(Kenkyū-buntansha)	黒川清東海大学, 医学部, 教授 (30167390)
Keywords	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
Research Abstract	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。

Research Products

(29 results)

All Other

All Publications (29 results)

[Publications] 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)
[Publications] 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)
[Publications] Miyata T, et al.: "Reactive carbonyl compound-related uremic toxicity(carbonyl stress)"Kidney Int. 59[Suppl 78]. 25-31 (2001)
[Publications] 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)
[Publications] Yamada K, et al.: "Clusterin is up-regulated in glomerular mesangial cells in complement-mediated injury"Kidney Int. 59. 137-146 (2001)
[Publications] Miyata T, et al.: "Reactive carbonyl compounds as uremic toxins"Contrib Nephrol. 133. 71-80 (2001)
[Publications] 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)
[Publications] Nangaku M, et al.: "Cloning of rodent megsin revealed its up-regulation on mesangioproliferative nephritis"Kidney Int. 60. 641-652 (2001)
[Publications] 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)
[Publications] 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)
[Publications] Suzuki D, et al.: "Carbonyl Stress,Type-2 diabetic nephropathy in Japan from bench to bedside"Contributions to Nephrology. 13. 36-45 (2001)
[Publications] 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)
[Publications] 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)
[Publications] 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)
[Publications] 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)
[Publications] 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)
[Publications] Morimoto K, et al.: "Cytoprotective role of heme oxygenase(HO)-1 in human kidney with various renal diseases"Kidney Int. 60. 1858-1866 (2001)
[Publications] 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)
[Publications] Kurokawa K, et al.: "Current issues and future perspectives of chronic renal failure"J Am Soc Nephrol. (in press).
[Publications] Miyata T, et al.: ""Carbonyl Stress"and long-term uremic complications"Advanced in Nephrology. (in press).
[Publications] Kurokawa K, et al.: "Future perspectives of chronic renal failure"Am J Kidney Dis. (in press).
[Publications] Ishibashi Y, et al.: "Glucose dialysate induces mitochondrial DNA damage in peritoneal mesothelial cells"Prit Dial Int. (in press).
[Publications] Asano M, et al.: "Renal tubular metabolism of protein-linked pentoisidine,an advanced glycation end product"Nephron. (in press).
[Publications] Miyata T, et al.: "Progressive mesangial expansion and hypercellularity in transgenic mice of mesangial cell-predominant serpin, megsin"J Clin Invest. (in press).
[Publications] Inagi R, et al.: "Efficient detoxification of carbonyl stress by the gloxalase system in peritoneal dialysis"Kidney Int. (in press).
[Publications] 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).
[Publications] 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)
[Publications] Nangaku M, et al.: "Forum Issue of ARS"Relevance of oxidative and carbonyl stress in uremia(in press).
[Publications] Miyata T, et al.: "Nutritional Management of Renal Disease"Carbonyl stress in uremia(in press).

2001 Fiscal Year Annual Research Report

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

Principal Investigator

宮田 敏男 東海大学, 医学部, 助教授 (10222332)

Research Products

[Publications] 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)

[Publications] 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)

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

[Publications] 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)

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

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

[Publications] 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)

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

[Publications] 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)

[Publications] 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)

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

[Publications] 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)

[Publications] 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)

[Publications] 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)

[Publications] 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)

[Publications] 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)

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

[Publications] 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)

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

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

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

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

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

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

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

[Publications] 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).

[Publications] 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)

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

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

宮田敏男東海大学, 医学部, 助教授 (10222332)