慢性腎不全にともなうミネラル骨代謝異常における新規活性および阻害分子の作用機序

• 研究課題/領域番号: 19590950
• 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: 神戸大学
• 研究代表者: 深川 雅史 神戸大学, 医学部附属病院, 准教授 (00211516)
• 研究分担者: 濱田 康弘 神戸大学, 医学部附属病院, 特定助教 (30397830)
• 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: 4,550千円 (直接経費: 3,500千円、間接経費: 1,050千円); 2008年度: 1,430千円 (直接経費: 1,100千円、間接経費: 330千円); 2007年度: 3,120千円 (直接経費: 2,400千円、間接経費: 720千円)
• キーワード: 人工透析学 / 骨代謝 / 腎不全 / 副甲状腺ホルモン / 糖尿病 / 酸化ストレス / インドキシル硫酸 / 骨芽細胞 / AGE / RAGE / 賢不全

研究概要

慢性腎臓病(Chronic Kidney Disease: CKD)とその最大の原因である糖尿病における骨代謝異常の機序,特に骨の副甲状腺ホルモン(PTH)に対する抵抗性と骨芽細胞機能抑制の発症機序について検討したところ,尿毒症物質であるインドキシル硫酸が有機酸トランスポーターを通じて細胞内に入り,酸化ストレスを惹起して,PTHの作用を減弱させることを示した.また,酸化ストレスは,糖尿病における骨芽細胞機能低下にも大きな役割を果たしていることが,糖尿病動物モデルや抗酸化物質過剰発現マウスを用いた実験で明らかになった.これらの知見は,CKDおける骨回転の調節異常の治療法につながると考えられる.

研究成果

• [雑誌論文] The calcimimetic R-568 retards progression of uremia-enhanced vascular calcification and atherosclerosis in apolipoprotein E deficient (apoE-/-) mice. Atherosclerosis (2009)
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• [雑誌論文] Oral charcoal adsorbent (AST-120) prevents the progression of cardiac damage in chronic kidney disease through the suppression of oxidative stress. Nephrol Dial Transplant (2009)
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• [雑誌論文] Pharmacokinetic target for ciclosporin A-based regimens in renal transplantation: Implications of maintaining 1,25-dihydroxyvitamin D3 synthesis. Clin Transplant (2009)
  • 著者名/発表者名: Sato T, Fukagawa M, Uchida K, Katayama A, Nagasaka T, Matsuoka S, Goto N, Tominaga Y, Kobayashi T, Nakao A
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• [雑誌論文] Thioredoxin-1 overexpression in transgenic mice attenuates streptozotocin-induced diabetic oeteoporosis: A novel role of oxidative stress and therapeutic implications. Bone (2009)
  • 著者名/発表者名: Hamada Y, Fujii H, Kitazawa R, Yodoi J, Kitazawa S, Fukagawa M
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  • 査読あり
• [雑誌論文] Cinacalcet (KRN 1493) effectively decreases serum intact PTH level with favorable control of serum phohphorus and calcium levels in Japanese dialysis patients. Nephrol Dial Transplant (2008)
  • 著者名/発表者名: Fukagawa M, Yumita S, Akizawa T, Uchida E, Tsukamoto Y, Iwasaki M, Koshikawa S, and KRN1493 study group
  • 雑誌名: 23 ページ: 328-335
  • 査読あり
• [雑誌論文] Direct calcitriol or its analogue injection improves abnormal gene expression of hyperplastic parathyroid gland in secondary hyperparathyroidism. Am J Nephrol (2008)
  • 著者名/発表者名: Shiizaki K, Fukagawa M, Yuan Q, Hatamura I, Nii-Kono T, Saji F, Shigematsu T, Akizawa T
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  • 査読あり
• [雑誌論文] Bone formation in the newly established non-obese type 2 diabetic model rats; Spontaneously Diabetic Torii (SDT) rats. Bone (2008)
  • 著者名/発表者名: Fujii H, Hamada Y, Fukagawa M
  • 雑誌名: 42 ページ: 372-379
  • 査読あり
• [雑誌論文] Effects of serum levels of calcium, phosphorus, and intact PTH on survival in chronic hemodialysis patients in Japan. Ther Aphr Dial (2008)
  • 著者名/発表者名: Nakai S, Akiba T, Kazama JJ, Yokoyama K, Fukagawa M. Tominaga Y, Iseki K, Tsubakihara Y
  • 雑誌名: 12 ページ: 49-54
  • 査読あり
• [雑誌論文] Alteration of duodenal iron absorption in adenine-induced renal failure rats: a possible mechanism of iron deficiency in chronic kidney disease patients with erythropoietin treatment. Nephrol Dial Transplant (2008)
  • 著者名/発表者名: Hamada Y, Nii-Kono T, Moriguchi Y, Higuchi M, Fukagawa M
  • 雑誌名: 23 ページ: 1886-1891
  • 査読あり
• [雑誌論文] Serum hepcidin as an indicator of iron status in dialysis patients. Ther Aphr Dial (2008)
  • 著者名/発表者名: Tsuchihashi D, Abe T, Komaba H, Fujii H, Hamada Y, Nii-Kono T, Tanaka M, Fukagawa M
  • 雑誌名: 12 ページ: 226-231
  • 査読あり
• [雑誌論文] Putative role of asymmetric dimethylarginine in microvascular disease of kidney and heart in hypertensive patients, Am J Hypertension (2008)
  • 著者名/発表者名: Fujii H, Takiuchi S, Kawano Y, Fukagawa M
  • 雑誌名: 21 ページ: 650-656
  • 査読あり
• [雑誌論文] Putative role of endothelial lipase in cardiovascular disease in dialysis patients with malnutrition and inflammation. Am J Nephrol (2008)
  • 著者名/発表者名: Fujii H, Fukuda A, Tanaka M, Kojima Y, Ishida T, Hirata K, Fukagawa M
  • 雑誌名: 28 ページ: 974-981
  • 査読あり
• [雑誌論文] Percutaneous ethanol injection therapy for advanced renal hyperparathyroidism in Japan: A 2004 survey by the Japanese Society for Parathyroid Intervention. NDT Plus (Supple) (2008)
  • 著者名/発表者名: Kakuta T, Fukagawa M, Kitaoka M, Koiwa F, Onoda N, Tominaga Y, Akizawa T, Kurokawa K
  • 雑誌名: 1
  • 査読あり
• [雑誌論文] Long-term prognosis (over 5 years) of parathyroid function in chronic dialysis patients after PEIT guided by ultrasonography. NDT Plus (Supple) (2008)
  • 著者名/発表者名: Tanaka R, Kakuta T, Koiwa F, Fukagawa M, Saito A
  • 雑誌名: 1
  • 査読あり
• [雑誌論文] Association between long-term efficacy of cinacalcet and parathyroid gland volume in haemodialysis patients with secondary hyperparathyroidism. NDT Plus (Supple) (2008)
  • 著者名/発表者名: Tanaka M, Nakanishi S, Komaba H, Itoh K, Matsushita K, Fukagawa M
  • 雑誌名: 1
  • 査読あり
• [雑誌論文] The whole-PTH/intact-PTH ratio is a useful predictor of severity of secondary hyperparathyroidism. NDT Plus (Supple) (2008)
  • 著者名/発表者名: Tanaka M, Komaba H, Itoh K, Matsushita K, Matsushita K, Hamada Y, Fujii H, Fukagawa M
  • 雑誌名: 1
  • 査読あり
• [雑誌論文] Relationship between the weight of parathyroid glands and their secretion of parathyroid hormone in hemodialysis patients with secondary hyperparathyroidism. Ther Aphre Dial (2008)
  • 著者名/発表者名: Kakuta T, Tanaka R, Kanai G, Miyamoto Y, Inagaki M, Suzuki H, Fukagawa M, Saito A
  • 雑誌名: 12 ページ: 385-390
  • 査読あり
• [雑誌論文] Bone formation in the newly established non-obese type 2 diabetic model rats ; Spontaneously Diabetic Torii (SDT)rats. (2008)
  • 著者名/発表者名: Fujii H, et al
  • 雑誌名: Bone 42 ページ: 372-379
  • 査読あり
• [雑誌論文] Alteration of duodenal iron absorption in adenine-induced renal failurerats : a possible mechanism of iron deficiency in chronic kidney disease patients with erythropoietin treatment. (2008)
  • 著者名/発表者名: Hamada Y, et al
  • 雑誌名: Nephrol Dial Transplant 23 ページ: 1886-1891
  • 査読あり
• [雑誌論文] Relationship between the weight of parathyroid glands and their secretion of parathyroid hormone in hemodialysis patients with secondary hyperparathyroidism. (2008)
  • 著者名/発表者名: Kakuta T, et al
  • 雑誌名: Ther Aphre Dial 12 ページ: 385-390
  • 査読あり
• [雑誌論文] Putative role of asymmetric dimethylarginine in microvascular disease of kidney and heart in hypertensive patients. (2008)
  • 著者名/発表者名: Fujii H, et al
  • 雑誌名: Am J Hypertens 21 ページ: 650-656
  • 査読あり
• [雑誌論文] The wholo-PTH/intact-PTH ratio is a useful predictor of severity of secondary hyperparathyroidism. (2008)
  • 著者名/発表者名: Tanaka M, et al
  • 雑誌名: NDT Plus 1 (Supple)
  • 査読あり
• [雑誌論文] Reduced dialysate calcium improves mineral metabolism in hemodialysis patients. Clin Nephrol (2007)
  • 著者名/発表者名: Fujimori A, Yorifuji M, Sakai M, Fukagawa M
  • 雑誌名: 67 ページ: 20-24
  • 査読あり
• [雑誌論文] A Possible role of thioredoxine interacting protein in the pathogenesis of streptozotocin-induced diabetic nephropathy. Kobe J Med Sci (2007)
  • 著者名/発表者名: Hamada Y, Fukagawa M
  • 雑誌名: 53 ページ: 53-61
  • 査読あり
• [雑誌論文] Indoxyl sulfate induced skeletal resistance to PTH in osteoblastic cells, Kidney Int (2007)
  • 著者名/発表者名: Nii-Kono T, Iwasaki Y, Yamato H, Fukagawa M
  • 雑誌名: 71 ページ: 738-743
  • 査読あり
• [雑誌論文] Histomorphometric analysis of diabetic osteopenia in streptozotocin-induced diabetic mice: a possible role of oxidative stress. Bone (2007)
  • 著者名/発表者名: Hamada Y, Kitazawa S, Kitazawa R, Fujii H, Kasuga M, Fukagawa M
  • 雑誌名: 40 ページ: 1408-1414
  • 査読あり
• [雑誌論文] Overexpression of thioredoxin 1 in transgenic mice suppresses development of diabetic nephropathy. Nephrol Dial Transplant (2007)
  • 著者名/発表者名: Hamada Y, Miyata S, Nii-Kono T, Kitazawa R, Kitazawa S, Higo S, Fukunaga M, Ueyama S, Nakamura H, Yodoi J, Fukagawa M, Kasuga M
  • 雑誌名: 22 ページ: 1547-1557
  • 査読あり
• [雑誌論文] Fibroblast growth factor-23 (FGF-23) in patints with transient hypoparathyroidism: Its important role in serum phosphate regulation. Endocrine J (2007)
  • 著者名/発表者名: Yamashita H, Yamazaki Y, Hasagawa H, Yamashita T, Fukumoto S, Shigematsu T, Kazama JJ, Fukagwa M, Noguchi S
  • 雑誌名: 54 ページ: 465-470
  • 査読あり
• [雑誌論文] Relationship between parathyroid hormone and cardiac abnormalities in chronic dialysis patients without cardiac disease, Internal Med (2007)
  • 著者名/発表者名: Fujii H, Kim J-I, Abe T, Umezu M, Fukagawa M
  • 雑誌名: 46 ページ: 1507-1512
  • 査読あり
• [雑誌論文] Indoxyl sulfate induced skeletal resistance to PTH in osteoblastic cells (2007)
  • 著者名/発表者名: Nii-Kono T, et. al.
  • 雑誌名: Kidney International 71 ページ: 738-743
  • 査読あり
• [雑誌論文] Histomorphometric analysis of diabetic osteopenia in streptozotocin-induced diabet ic mice: a possible role of oxidative stress (2007)
  • 著者名/発表者名: Hamada Y, et. al.
  • 雑誌名: Bone 40 ページ: 1408-1414
  • 査読あり
• [雑誌論文] Overexpression of thioredoxin I in transgenic mice suppresses development of diabetic nephropathy (2007)
  • 著者名/発表者名: Hamada Y, et. al
  • 雑誌名: Nephrol Dial Transplant 22 ページ: 1547-1557
  • 査読あり
• [学会発表] V International Symposium: Advances in Bone and Mineral Disorders in CKD (2009)
  • 著者名/発表者名: Fukagawa M
  • 学会等名: FGF23, phosphate, and VDRE in dialysis
  • 発表場所: Oviedo, Spain
  • 年月日: 2009-05-20
• [学会発表] Workshop of Earthquake Related AKI, co-organized ISN COMGAN & Chinese Society of Nephrology (2008)
  • 著者名/発表者名: Fukagawa M
  • 学会等名: Nephrology in earthquakes: Sharing experiences and information
  • 発表場所: Chengdu, China
  • 年月日: 2008-12-16
• [学会発表] Vitamin D receptor activator (VDRA) treatment attenuate increased oxidative stress in hemodialysis patients (2008)
  • 著者名/発表者名: Tanaka M, Tokunaga T, Komaba H, Itoh K, Matsushita K, Maruyama T, Otagiri M, Fukagawa M
  • 学会等名: America Society of Nephrology
  • 発表場所: Philadelphia, USA
  • 年月日: 2008-11-07
• [学会発表] Functional induction of target genes in parathyroid cell by direct injection (2008)
  • 著者名/発表者名: Shiizaki K, Hatamura I, Nakazawa E, Saji F, Imazu Y, Watanabe Y, Ueda Y, Fukagawa M, Akizawa T, Kusano E
  • 学会等名: American Society of Nephrology
  • 発表場所: Philadelphia, USA
  • 年月日: 2008-11-07
• [学会発表] Different roles of oxidative stress and asymmetric dimethylarginine for the progression of diabetic nephropathy in the newly established non-obese type 2 diabetic model rata: Spontaneously Diabetic Torii (SDT) rats (2008)
  • 著者名/発表者名: Fujii H, Hamada Y, Komaba H, Kitazawa R, Kitazawa S, Fukagawa M
  • 学会等名: American Society of Nephrology
  • 発表場所: Philadelphia, USA
  • 年月日: 2008-11-07
• [学会発表] Sevelamer hydrochloride elevates serum homocysteine levels through inhibiting absorption of folic acid in chronic dialysis (2008)
  • 著者名/発表者名: Goto S, Fujii H, Kim J-I, Fukagwa M
  • 学会等名: American Society of Nephrology
  • 発表場所: Philadelphia, USA
  • 年月日: 2008-11-07
• [学会発表] Putative roles of receptors for AGEs (RAGE) in bone metabolism under non-diabetic and diabetic (2008)
  • 著者名/発表者名: Hamada Y, Goto S, Komaba H, Fujii H, Fukagawa M
  • 学会等名: American Society of Nephrology
  • 発表場所: Philadelphia, USA
  • 年月日: 2008-11-07
• [学会発表] Treatment of various rebal involvements associated with multicentric Castleman's disease with anti-interleukin-6 receptor antibody (Tocilzumab) (2008)
  • 著者名/発表者名: Komaba H, Nakazawa T, Tsuji G, Yamaguchi Y, Kumagai S, Fukagawa M
  • 学会等名: American Society of Nephrology
  • 発表場所: Philadelphia, USA
  • 年月日: 2008-11-07
• [学会発表] Putative roles of receptors for AGEs (RAGE) in bone metabolism under non-diabetic and diabetic condition (2008)
  • 著者名/発表者名: Hamada Y, et al
  • 学会等名: American Society of Nephrology
  • 発表場所: Philadelphia, USA
  • 年月日: 2008-11-07
• [学会発表] Vitamin D receptor activator (VDRA)treatment attenuate increased oxidative stress in hemodialysis patients (2008)
  • 著者名/発表者名: Tanaka M, el al
  • 学会等名: American Society of Nephrology
  • 発表場所: Philadelphia, USA
  • 年月日: 2008-11-07
• [学会発表] Functional induction of target genes in parathyroid cell by direct injection technique. (2008)
  • 著者名/発表者名: Shiizaki K, et al
  • 学会等名: American Society of Nephrology
  • 発表場所: Philadelphia, USA
  • 年月日: 2008-11-07
• [学会発表] Sevelamer hydrochloride elevates serum homocycteine levels through in hibiting absorption of folic acid in chronic dialysis patients. (2008)
  • 著者名/発表者名: Goto S, et al
  • 学会等名: American Society of Nephrology
  • 発表場所: Philadelphia, USA
  • 年月日: 2008-11-07
• [学会発表] Kidney dysfunction distuebs collagen maturation in adynamic bone disease as assessed by confocal laser raman spectroscopy (2008)
  • 著者名/発表者名: Iwasaki Y, Yamato H, Fukagawa M
  • 学会等名: American Society for Bone and Mineral Research
  • 発表場所: Montreal, Canada
  • 年月日: 2008-09-14
• [学会発表] Functional induction of target genes in parathyroid cell by direct injection technique (2008)
  • 著者名/発表者名: Shiizaki K, Hatamura I, Nalazawa E, Iwazu Y, Watanabe Y, Fukagawa M, Akizawa T, Kusano E
  • 学会等名: American Society for Bone and Mineral Research
  • 発表場所: Montreal Canada
  • 年月日: 2008-09-14
• [学会発表] FGF-23 in CKD, ectopic calcification, post-transplantation hypophosphatemia, and nephrolitiasis. (2008)
  • 著者名/発表者名: Fukagawa M
  • 学会等名: Symposium, XLV ERA-EDTA Congress
  • 発表場所: Stockholm, Sweden
  • 年月日: 2008-05-12
• [学会発表] CKD-MBD in diabetes: from bench to bedside (2008)
  • 著者名/発表者名: Fukagawa M
  • 学会等名: Updates on CKD-MBD, Korea University
  • 発表場所: Seoul, Korea
  • 年月日: 2008-04-26
• [学会発表] PTH assay: from pronciple to practice (2008)
  • 著者名/発表者名: Fukagawa M
  • 学会等名: Updates on CKD-MBD, Korea University, Seoul
  • 発表場所: Seoul, Korea
  • 年月日: 2008-04-26
• [学会発表] Overexpression of Thioredoxin-1, a Major Intracellular Antioxidant, Attenuates Streptozotocin-Induced Diabetic Osteopenia (2007)
  • 著者名/発表者名: Hamada Y, et. al.
  • 学会等名: アメリカ腎臓学会
  • 発表場所: サンフランシスコ
  • 年月日: 2007-11-06
• [学会発表] Asymmetric dimethylarginine reflects an incipient atherosclerosis in both kidney and heart (2007)
  • 著者名/発表者名: Fujii H, Takiuchi S, Kawano Y, Fukagawa M
  • 学会等名: ERA-EDTA Congress
  • 発表場所: Barcelona, Spain
  • 年月日: 2007-06-22
• [学会発表] Randomized, placebo-controlled trial of cinacalcet (KRN1493) in Japanese dialysis patients with more severe hyperparathyroidism and longer dialysis (2007)
  • 著者名/発表者名: Fukagawa M, Yumita S, Akizawa T, Tsukamoto Y, Uchida E, Iwasaki M, Koshikawa S
  • 学会等名: ERA-EDTA Congress
  • 発表場所: Barcelona, Spain
  • 年月日: 2007-06-22
• [学会発表] 1-84PTH/intact PTH ratio is a useful predictor of the severity of secondary hyperparathyroidism (2007)
  • 著者名/発表者名: Tanaka M, Itoh K, Matsushita K, Matsushita K, Hamada Y, Fujii H, Fukagawa M
  • 学会等名: ERA-EDTA Congress
  • 発表場所: Barcelona, Spain
  • 年月日: 2007-06-22
• [図書] Fluid & Electrolyte Disorders, in 2008 Current Medical Diagnosis & Treatment(McPhee SJ, Papadakis, MA) (2009)
  • 著者名/発表者名: Cho KC, Fukagawa M, Kurokawa K
  • 出版者: Lange Medical Books/McGrow Hill, New York
• [図書] Fluid & Electrolyte Disorders, in 2008 Current Medical Diagnosis & Treatment(McPhee SJ, Papadakis, MA) (2008)
  • 著者名/発表者名: Fukagawa M, Kurokawa K, Papadakis MA
  • 出版者: Lange Medical Books/McGrow Hill, New York
• [図書] (2008)
  • 著者名/発表者名: Fukagawa M, Tanaka M
  • 出版者: Hypophosphatemia, Encyclopedic reference of molecular mechanism of disease,
• [図書] 副甲状腺インターペンションガイド (2008)
  • 著者名/発表者名: 副甲状腺インターペンション研究会
  • 総ページ数: 64
  • 出版者: 文光堂
• [図書] Fluid & Electrolyte Disorders, in 2007 Current Medical Diagnosis & Treatment(Tierney LM Jr, McPhee SJ,Papadakis MA) (2007)
  • 出版者: Lange Medical Books/McGrow Hill, New York
• [図書] ガイドラインサポートブック:慢性腎臓病に伴う骨ミネラル代謝異常 (2007)
  • 著者名/発表者名: 深川雅史
  • 総ページ数: 344
  • 出版者: 医薬ジャーナル社
• [図書] Imaging of intervension pf parathyroid hyperplasia, in Spectrum of Renal Osteodystrophy and Vascular Caicification in Uremia( Olgaar K, Silver J, Salusky I)
  • 著者名/発表者名: Komaba H, Tanaka M, Fukagawa M
  • 出版者: Oxford University Press