慢性腎臓病におけるADMA代謝と微小血管障害-腎機能障害と蛋白尿に関して-

• 研究課題/領域番号: 19590971
• 研究種目: 基盤研究(C)
• 配分区分: 補助金
• 応募区分: 一般
• 研究分野: 腎臓内科学
• 研究機関: 久留米大学
• 研究代表者: 奥田 誠也 久留米大学, 医学部, 教授 (80158823)
• 研究分担者: 上田 誠二 久留米大学, 医学部, 講師 (80322593)
• 研究期間 (年度): 2007 – 2008
• 研究課題ステータス: 完了 (2008年度)
• 配分額: 4,290千円 (直接経費: 3,300千円、間接経費: 990千円); 2008年度: 2,080千円 (直接経費: 1,600千円、間接経費: 480千円); 2007年度: 2,210千円 (直接経費: 1,700千円、間接経費: 510千円)
• キーワード: 慢性腎臓病 / CKD / 一酸化窒素 / 内皮機能障害 / 蛋白尿 / ADMA DDAH / DDAH / ADMA / 心血管病 / NO

研究概要

Asymmetric dimethylarginine(ADMA)は一酸化窒素(NO)の内因性合成阻害物質で、血管内皮機能障害により心血管病に密接に関わる。慢性腎臓病(CKD)では血中ADMA 濃度が上昇し、このことがCKDで頻度が増加する心血管病に関わると考えられる。一方、CKDにおける腎機能障害の進行にも内皮機能は重要と思われ、CKD患者では蛋白尿、腎機能低下に伴ってADMAが増加している。本研究ではCKDモデルラットにADMAの分解酵素であるDDAHを強制発現させ、ADMAを抑制することにより、腎機能、蛋白尿および腎組織病変も著明に改善することを明らかにし、ADMA-DDAH系をターゲットにした治療がCKD治療に有望であることを示した。

研究成果

• [雑誌論文] Involvement of asymmetric dimethylarginine (ADMA) in tubulointerstitial ischemia in early phase of diabetic nephropathy. (2009)
  • 著者名/発表者名: Shibata R, Ueda S, Yamagishi S, Kaida Y, Matsumoto Y, Fukami K, Hayashida A, Matsuoka H, Kato S, Kimoto M, Okuda S.
  • 雑誌名: Nephrol Dial Transplant. 24 ページ: 1162-1169
  • 査読あり
• [雑誌論文] Administration of pigment epithelium-derived factor (PEDF) reduces proteinuria by suppressing decreased nephrin and increased VEGF expression in the glomeruli of adriamycin-injected rats. (2009)
  • 著者名/発表者名: Fujimura T, Yamagishi S, Ueda S, Fukami K, Shibata R, Matsumoto Y, Kaida Y, Hyayashida A, Koike K, Matsui T, Nakamura K, Okuda S.
  • 雑誌名: Nephrol Dial Transplant. 24 ページ: 1397-1406
  • 査読あり
• [雑誌論文] Clinical utility of acarbose, alpha-glucosidase inhibitor on cardiometabolic disorders. (2009)
  • 著者名/発表者名: Yamagishi S, Matsui T, Ueda S, Fukami K, Okuda S.
  • 雑誌名: Curr Drug Metab. 10 ページ: 159-163
  • 査読あり
• [雑誌論文] Involvement of ADMA in tubulointerstitial ischemia in early phase of diabetic nephropathy (2009)
  • 著者名/発表者名: Shibata R, Okuda S
  • 雑誌名: Nephrol Dial Transplant 24 ページ: 1162-1169
  • 査読あり
• [雑誌論文] Circulating Matrix Metalloproteinase-2 is an independent correlate of proteinuria in patients with chronic kidney disease. (2008)
  • 著者名/発表者名: Nagano M, Fukami K, Yamagishi SI, Ueda S, Kaida Y, Matsumoto T, Yoshimura J, Hazama T, Takamiya Y, Kusumoto T, Gohara S, Tanaka H, Adachi H, Okuda S.
  • 雑誌名: Am J Nephrol. 29 ページ: 109-115
  • 査読あり
• [雑誌論文] Role of Asymmetric Dimethylarginine (ADMA) in Diabetic Vascular Complications. (2008)
  • 著者名/発表者名: Yamagishi S, Ueda S, Nakamura K, Matsui T, and Okuda S.
  • 雑誌名: Curr Pharm Des 14 ページ: 2613-2618
  • 査読あり
• [雑誌論文] Agents that block advanced glycation end product (AGE)-RAGE (receptor for AGEs)-oxidative stress system: a novel therapeutic strategy for diabetic vascular complications. (2008)
  • 著者名/発表者名: Yamagishi S, Nakamura K, Matsui T, Ueda S, Fukami K, Okuda S.
  • 雑誌名: Expert Opin Investig Drugs. 17 ページ: 983-96
  • 査読あり
• [雑誌論文] Implication of asymmetric dimethylarginine (ADMA) in endothelial cell growth process in atherosclerosis. (2008)
  • 著者名/発表者名: Ueda S, Yamagishi S, Fukami K, Hayashida A, Kaida Y, Takamiya Y, Okuda S.
  • 雑誌名: Cell Growth Processes: New Research. (Nova publishers) Chapter IV ページ: 123-137
  • 査読あり
• [雑誌論文] Role of AGEs in diabetic nephropathy. (2008)
  • 著者名/発表者名: Fukami K, Yamagishi S, Ueda S, Okuda S.
  • 雑誌名: Current Pharm Design 14 ページ: 946-952
  • 査読あり
• [雑誌論文] Role of advanced glycation end products (AGEs) and oxidative stress in diabetic retinopathy. (2008)
  • 著者名/発表者名: Yamagishi S, Ueda S, Matsui T, Nakamura K, Okuda S.
  • 雑誌名: Curr Pharm Des. 14 ページ: 962-8
  • 査読あり
• [雑誌論文] Pleiotropic effects of atorvastatin of vascular injury in diabetes. (2008)
  • 著者名/発表者名: Yamagishi S, Nakamura K, Matsui T, Ueda S, Fukami K, Okuda S.
  • 雑誌名: BDL Cholesterol: Targets, Control and Therapy.
  • 査読あり
• [雑誌論文] Olmesartan blocks advanced glycation end products (AGEs)-induced angiogenesis in vitro by suppressing receptor for AGEs (RAGE) expression (2008)
  • 著者名/発表者名: Yamagishi S, Matsui T, Nakamura K, Inoue H, Takeuchi M, Ueda S, Fukami K, Okuda S, Imaizumi T.
  • 雑誌名: Microvasc Res 75 ページ: 130-134
  • 査読あり
• [雑誌論文] Aqueous humor levels of asymmetric dimethylarginine (ADMA) are positively associated with monocyte chemoattractant protein-1 (MCP-1) in patients with uveitis. (2008)
  • 著者名/発表者名: Yoshida Y, Yamagishi S, Ueda S, Okuda S, Yamakawa R.
  • 雑誌名: Br J Ophthalmol. 92(1) ページ: 93-4
  • 査読あり
• [雑誌論文] Circulating MMP-2 is an independent correlate of proteinuria in patients with chronic kidney disease (2008)
  • 著者名/発表者名: Nagano M, Okuda S
  • 雑誌名: Am J Nephrol 29 ページ: 109-115
  • 査読あり
• [雑誌論文] Asymmetric dimethylarginine (ADMA) in diabetic vascular complications (2008)
  • 著者名/発表者名: Yamagishi S, Okuda S
  • 雑誌名: Curr Pharm Des 14 ページ: 2613-2618
  • 査読あり
• [雑誌論文] Asymmetric dimethylarginine (ADMA) may be a missing link between cardiovascular disease (CVD) and chronic kidney disease (CKD). (2007)
  • 著者名/発表者名: Ueda S, Yamagishi S, Kaida Y, Okuda S.
  • 雑誌名: Nephrology 12 ページ: 582-590
  • 査読あり
• [雑誌論文] Dimethylarginine dimethylaminohydrolase prevents progression of renal dysfunction by inhibiting loss of peritubular capillaries and tubulointerstitial fibrosis in a rat model of chronic kidney disease. (2007)
  • 著者名/発表者名: Matsumoto Y, Ueda S, Yamagishi S, Matsuguma K, Shibata R, Fukami K, Matsuoka H, Imaizumi T, Okuda S.
  • 雑誌名: J Am Soc Nephrol. 18 ページ: 1525-1533
  • 査読あり
• [雑誌論文] Asymmetric dimethylarginine (ADMA) and endothelial dysfunction in patients with chronic kidney disease. (2007)
  • 著者名/発表者名: Ueda S, Yamagishi S, Takamiya Y, Kaida Y, Okuda S.
  • 雑誌名: Research Advances in Nephrology. 1 ページ: 1-12
  • 査読あり
• [雑誌論文] Aqueous humor levels of asymmetric dimethylarginine (ADMA) are correlated with pigment epithelium-derived factor (PEDF) in patients with uveitis. (2007)
  • 著者名/発表者名: Yoshida Y, Yamagishi S, Ueda S, Yoshimura K, Okuda S, Yamakawa R.
  • 雑誌名: J Int Med Res 35 ページ: 892-895
  • 査読あり
• [雑誌論文] Role of asymmetric dimethylarginine (ADMA) in chronic kidney disease (2007)
  • 著者名/発表者名: Ueda S, Yamagishi S, Matsumoto Y, Okuda S.
  • 雑誌名: Current Enzyme Inhibition 3 ページ: 284-290
  • 査読あり
• [雑誌論文] Pigment epithelium-derived factor prevents advanced glycation end products-elicited endothelial nitric oxide synthase reduction through its ant-oxidative properties. (2007)
  • 著者名/発表者名: Yamagishi S, Ueda S, Matsui T, Nakamura K, Imaizumi T, Takeuchi M, Okuda S.
  • 雑誌名: Protein Pept Lett 14 ページ: 832-5
  • 査読あり
• [雑誌論文] Olmesartan blocks advanced glycation end product (AGE)-evoked inflammatory reactions in endothelial cells by suppressing reactive oxygen species generation. (2007)
  • 著者名/発表者名: Yamagishi S, Matsui T, Nakamura K, Inoue H, Takeuchi M, Ueda S, Okuda S, Imaizumi T.
  • 雑誌名: Ophthalmic Res 40 ページ: 10-15
  • 査読あり
• [雑誌論文] Food-derived advanced glycation end products (AGEs): A novel therapeutic target for various disorders. (2007)
  • 著者名/発表者名: Yamagishi S, Ueda S, Okuda S.
  • 雑誌名: Current Pharmaceutical Design 13 ページ: 2832-6
  • 査読あり
• [雑誌論文] Asymmetric dimethylarginine (ADMA) is a novel emerging risk factor for cardiovascular disease and development of renal injury in chronic kidney disease. (2007)
  • 著者名/発表者名: Ueda S, Yamagishi S, Matsumoto Y, Fukami K, Okuda S.
  • 雑誌名: Clin Exp Nephrol 11 ページ: 115-121
  • NAID: 10024140370
  • 査読あり
• [雑誌論文] A possible involvement of crosstalk between advanced glycation end products (AGEs) and asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor in accelerated atherosclerosis in diabetes (2007)
  • 著者名/発表者名: Yamagishi S, Ueda S, Okuda S.
  • 雑誌名: Med Hypotheses 69 ページ: 922-4
  • 査読あり
• [雑誌論文] Molecular mechanisms of diabetic nephropathy and its therapeutic intervention. (2007)
  • 著者名/発表者名: Yamagishi S, Fukami K, Ueda S, Okuda S.
  • 雑誌名: Current Drug Targets 8 ページ: 952-9
  • 査読あり
• [雑誌論文] Novel therapeutic targets for diabetic nephropathy. (2007)
  • 著者名/発表者名: Fukami K, Yamagishi S, Ueda S, Okuda S.
  • 雑誌名: Endocr Metab Immune Disord Drug Targets 7 ページ: 83-92
  • 査読あり
• [雑誌論文] Pitavastatin inhibits lysophosphatidic acid-induced proliferation and monocyte chemoattractant protein-1 expression in aortic smooth muscle cells by suppressing Rac-1-mediated reactive oxygen species generation. (2007)
  • 著者名/発表者名: Kaneyuki U, Ueda S, Yamagishi SI, Kato S, Fujimura T, Shibata R, Hayashida A, Yoshimura J, Kojiro M, Oshima K, Okuda S.
  • 雑誌名: Vascul Pharmacol. 46 ページ: 286-292
  • 査読あり
• [雑誌論文] Increased levels of IgG antibodies against peptides of the prostate stem cell antigen in the plasma of pancreatic cancer patients. (2007)
  • 著者名/発表者名: Tanaka M, Komatsu N, Terakawa N, Yanagimoto Y, Oka M, Sasada T, Mine T, Gouhara S, Shichijo S, Okuda S, Itoh K.
  • 雑誌名: Oncol Rep. 18 ページ: 161-166
  • 査読あり
• [雑誌論文] Adult-onset acute tubulointerstitial nephritis and uveitis with fanconi syndrome. Case report and review of the literature. (2007)
  • 著者名/発表者名: Koike K, Iida S, Usui M, Matsumoto Y, Fukami K, Ueda S, Tamaki K, Kato S, Okuda S.
  • 雑誌名: Clin Nephrol. 67 ページ: 255-9
  • 査読あり
• [雑誌論文] Mesangiolytic glomerulopathy after radiotherapy and chemotherapy of gastric lymphoma. (2007)
  • 著者名/発表者名: Yoshimura J, Kato S, Tamaki K, Kohno K, Kaneyuki U, Maeda M, Saikusa-Itoh Y, Hayashida A, Iida S, Suefuji H, Okuda S.
  • 雑誌名: Intern Med. 46(22) ページ: 1861-1865
  • NAID: 130000075926
  • 査読あり
• [雑誌論文] Nodular Glomerulosclerosis in patients without any manifestation of diabetes mellitus. (2007)
  • 著者名/発表者名: Sanai T, Okuda S, Yoshimitsu T, Oochi N, Kumagai H, Katafuchi R, Harada A, Chihara J, Abe T, Nakamoto M, Hirakata H, Onoyama K, Iida M.
  • 雑誌名: NEPHROLOGY 12 ページ: 69-73
  • 査読あり
• [雑誌論文] Dimethylarginine dimethylaminohydrolase prevents progression of renal dysfunction by inhibiting loss of peritubular capillaries and tubulointers titial fibrosis in a rat model of chronic kidney disease (2007)
  • 著者名/発表者名: Okuda S, et. al.
  • 雑誌名: J Am Soc Nephrol 18 ページ: 1525-1533
  • 査読あり
• [雑誌論文] Involvement of asymmetric dimethylarginine (ADMA) in glomerular capillary loss and sclerosis in a rat model of chronic kidney disease (CKD)
  • 著者名/発表者名: Ueda S, Yamagishi S, Matsumoto Y, Kaida Y, Fujimi-Hayashida A, Koike K, Tanaka H, Fukami K, Okuda S.
  • 雑誌名: Life Sciences in press
  • 査読あり
• [学会発表] Possible involvement od albuminuria-alicied ADMA accumulation in accelerated atherosclerosis in CKD (2008)
  • 著者名/発表者名: Kaida Y, Okuda S
  • 学会等名: 4^<th> International symposium on ADMA
  • 発表場所: Bregenz
  • 年月日: 2008-08-29
• [学会発表] ADMA in chronic kidney disease (2007)
  • 著者名/発表者名: Okuda, et. al.
  • 学会等名: Europian Congress of Dialysis, Transplantation and Nephrology
  • 発表場所: バルセロナ
  • 年月日: 2007-07-22
• [図書] Cell Growth Processes : New research (2008)
  • 著者名/発表者名: Ueda S, Okuda S
  • 出版者: Nova publisher