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Exploration of pathogenesis of diabetic complications using transgenic mice and attempts of gene therapy

Research Project

Project/Area Number 14370073
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Experimental pathology
Research InstitutionHirosaki University

Principal Investigator

YAGIHASHI Soroku  Hirosaki University, School of Medicine, Professor, 医学部, 教授 (40111231)

Co-Investigator(Kenkyū-buntansha) WADA Ryuichi  Hirosaki University, School of Medicine, Associate Professor, 医学部, 助教授 (20260408)
MIZUKAMI Hiroki  Hirosaki University, School of Medicine, Assistant, 医学部, 助手 (00374819)
馬場 正之  弘前大学, 医学部, 助教授 (90106849)
山岸 晋一朗  弘前大学, 医学部, 講師 (80301026)
八木橋 法登  弘前大学, 医学部, 講師 (10250622)
黒滝 日出一  弘前大学, 医学部, 助教授 (40215108)
Project Period (FY) 2002 – 2005
Project Status Completed (Fiscal Year 2005)
Budget Amount *help
¥13,900,000 (Direct Cost: ¥13,900,000)
Fiscal Year 2005: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2004: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2003: ¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 2002: ¥8,100,000 (Direct Cost: ¥8,100,000)
KeywordsPolyol pathway / Aldose reductase / Glycation / RAGE / AGE / Neuropathy / Target therapy / Diabetic complications / 合併症 / 遺伝子改変動物 / 細胞傷害機構 / 血管障害 / ニューロパチー
Research Abstract

To explore the mechanisms of diabetic complications and to establish the direction for the prevention and treatment of them, we studied biochemical, physiological and pathological changes in microvessels and peripheral nerve tissues using recently developed transgenic animal models. In this study, we used transgenic mice overexpressing human aldose reductase (AR) and knockout mice that were deficient of AR to examine the role of polyol pathway. On the other hand, transgenic mice that overexpress receptor for advanced glycation endproducts (RAGE) were used to see the effects of RAGE overexpression in the endothelial cells on the development of diabetic complications. These mouse models were made diabetic by intravenous injection of streptozotocin and followed for 16 weeks. The diabetic AR mice exhibited marked depression of protein kinase C (PKC) activity in the nerve while PKC activity was contrariwise elevated in vascular tissues. These changes were due to reduced membrane expression … More of PKC-alpha in the nerve and increased membrane expression of PKC-beta in vascular tissues. These alterations were associated with significant functional and structural pathology in nerve and vessels in diabetic animals and not found in diabetic AR-knockout mice. Inhibitors for AR effectively prevented all the changes. Thus, it was concluded that AR plays a crucial role in the cause of diabetic complications and its inhibition is effective for the prevention and treatment. However, under very severe hyperglycemia, even AR knockout mice could not escape the pathological changes of diabetic complications and other mechanisms were thought to exert for tissue injury. As one possible mechanism, RAGE overexpression induced more severe tissue damage compared to control diabetic mice, thus suggesting the implication of AGE-RAGE interaction for the development of diabetic complications. The current series of studies clearly demonstrated the multiple factors implicating in the cause of diabetic complications and we consider that multi-facet directions for the prevention and treatment will be essential for the clinical applications. Less

Report

(5 results)
  • 2005 Annual Research Report   Final Research Report Summary
  • 2004 Annual Research Report
  • 2003 Annual Research Report
  • 2002 Annual Research Report
  • Research Products

    (36 results)

All 2006 2005 2004 2003 Other

All Journal Article (21 results) Book (1 results) Publications (14 results)

  • [Journal Article] Prolonged ischemic conduction failure after reperfusion in diabetic nerve.2006

    • Author(s)
      Baba M, Nukdada H, McMorran D, Takahashi K, Wada R, Yagihashi S.
    • Journal Title

      Muscle Nerve 33・3

      Pages: 350-355

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Prolonged ischemic conduction failure after reperfusion in diabetic nerve.2006

    • Author(s)
      Baba M, Nukada H, McMorran D, Takahashi K, Wada R, Yagihashi S
    • Journal Title

      Muscle Nerve 33

      Pages: 350-355

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Role of advanced glycation endproducts and their receptors in development of diabetic neuropathy.2005

    • Author(s)
      Wada R, Yagihashi S.
    • Journal Title

      Ann NY Acad Sci 1043

      Pages: 598-604

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Role of advanced glycation endproducts and their receptors in development of diabetic neuropathy.2005

    • Author(s)
      Wada R, Yagihashi S
    • Journal Title

      Ann NY Acad Sci 1043

      Pages: 598-604

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Prolonged ischemic conduction failure after reperfusion in diabetic nerve.2005

    • Author(s)
      Baba M, Yagihashi S, et al.
    • Journal Title

      Muscle Nerve 33(3)

      Pages: 350-355

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Role of advanced glycation end products and their receptors in development of diabetic neuropathy.2005

    • Author(s)
      Wada R, Yagihashi S.
    • Journal Title

      Ann N Y Acad Sci 1043

      Pages: 598-604

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Transgenic expression of BACH1 transcription factor results in megakaryocytic impairment.2005

    • Author(s)
      Toki T, Yagihashi S, et al.
    • Journal Title

      Blood 105(8)

      Pages: 3100-3108

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Effects of polyol pathway hyperactivity on protein kinase C activity, nociceptive peptide expression, and neuronal structure in dorsal root ganglia in diabetic mice.2004

    • Author(s)
      Uehara K, Yamagishi S, Chin S, Yagihashi S.
    • Journal Title

      Diabetes 53・12

      Pages: 3239-3247

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Peripheral nerve endoneurial microangiopathy and necrosis in rats with insulinoma.2004

    • Author(s)
      Sugimoto K, Shoji M, Yasujima M, Suda T, Yagihashi S.
    • Journal Title

      Acta Neuropathol 108・6(Berl)

      Pages: 503-514

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Reduced cell replication and induction of apoptosis by advanced glycation end products in rat Schwann cells.2004

    • Author(s)
      Sekido H, Suzuki T, Jomori T, Takeuchi M, Yabe-Nishimura C, Yagihashi S.
    • Journal Title

      Biochem Biophys Res Commun 320・1

      Pages: 214-248

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Effects of polyol pathway hyperactivity on protein kinase C activity, nociceptive peptide expression, and neuronal structure in dorsal root ganglia in diabetic mice.2004

    • Author(s)
      Uehara K, Yamagishi S, Otsuki S, Chin S, Yagihashi S
    • Journal Title

      Diabetes 53

      Pages: 3239-3247

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Peripheral nerve endoneurial microangiopathy and necrosis in rats with insulinoma.2004

    • Author(s)
      Sugimoto K, Shoji M, Yasujima M, Suda T, Yagihashi S
    • Journal Title

      Acta Neuropathol (Berl) 108

      Pages: 503-514

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Reduced cell replication and induction of apoptosis by advanced glycation end products in rat Schwann cells.2004

    • Author(s)
      Sekido H, Suzuki T, Jomori T, Takeuchi M, Yabe-Nishimura C, Yagihashi S
    • Journal Title

      Biochem Biophys Res Commun 320

      Pages: 214-248

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Effects of polyol pathway hyperactivity on protein kinase C activity, nociceptive peptide expression, and neuronal structure in dorsal root ganglia in diabetic mice.2004

    • Author(s)
      Uehara K
    • Journal Title

      Diabetes 53・12

      Pages: 3239-3247

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Peripheral nerve endoneurial microangiopathy and necrosis in rats with insulinoma.2004

    • Author(s)
      Sugimoto K
    • Journal Title

      Acta Neuropathol(Berl) 108・6

      Pages: 503-514

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Reduced cell replication and induction of apoptosis by advanced glycation end products in rat Schwann cells2004

    • Author(s)
      Sekido H
    • Journal Title

      Biochem Biophys Res Commun 320・1

      Pages: 241-248

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Promoter methylation and protein expression of the E-cadherin gene in the clinicopathologic assessment of adenoid cystic carcinoma2004

    • Author(s)
      Maruya S
    • Journal Title

      Mod Pathol 17・6

      Pages: 637-645

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Nitric oxide generation and poly(ADP ribose) polymerase activation precede beta-cell death in rats with a single high-dose injection of streptozotocin2004

    • Author(s)
      Wada R
    • Journal Title

      Virchows Arch 444・4

      Pages: 375-382

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Expression of retinoic acid-inducible gene-I in vascular smooth muscle cells stimulated with interferon-gamma2004

    • Author(s)
      Imaizumi T
    • Journal Title

      Life Sci. 75・10

      Pages: 1171-1180

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Differential influence of increased polyol pathway on protein kinase C expressions between endoneurial and epineurial tissues in diabetic mice.2003

    • Author(s)
      Yamagishi S, Uehara K, Otsuki S, Yagihashi S.
    • Journal Title

      J Neurochem 87・2

      Pages: 497-507

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Differential influence of increased polyol pathway on protein kinase C expressions between endoneurial and epineurial tissues in diabetic mice.2003

    • Author(s)
      Yamagishi S, Uehara K, Otsuki S, Yagihashi S:
    • Journal Title

      J Neurochem 87

      Pages: 497-507

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Book] 臨床医のための糖尿病病理2004

    • Author(s)
      八木橋 操六
    • Total Pages
      241
    • Publisher
      診断と治療社
    • Related Report
      2004 Annual Research Report
  • [Publications] Shin-Ichiro Yamagishi: "Differential influence of increased polyol pathway on protein kinase C expressions between endoneurial and epineurial tissues in diabetic mice"J Neurochem. 87(2). 493-507 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Sinichiro Maruya: "Expression of p16 protein and hypermethylation status of its promoter gene in adenoid cystic carcinoma of the head and neck"ORL J Otorhinolaryngol Relat Spec. 65(1). 26-32 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Soroku Yagihashi: "Diabetic microangiopathy : pathology and current understanding of its pathogenesis"Verh Dtsch Ges Pathol. 81(1). 91-100 (2002)

    • Related Report
      2003 Annual Research Report
  • [Publications] Ryuichi Wada: "Intracytoplasmic immunoglobulin crystals in follicular lymphoma"Human Pathology. 33(11). 1141-1144 (2002)

    • Related Report
      2003 Annual Research Report
  • [Publications] 八木橋 操六: "糖尿病性神経障害の病理-ここ10年間の新知見を中心に-"日本臨床. 60(Suppl10). 204-208 (2002)

    • Related Report
      2003 Annual Research Report
  • [Publications] Yoshirou Kitahara: "Decreased blood glucose excursion by nateglinide ameliorated neuropathic changes in Goto-Kakizaki rats, an animal model of non-obese type 2 diabetes"Metabolism. 51(11). 1452-1457 (2002)

    • Related Report
      2003 Annual Research Report
  • [Publications] 八木橋 操六: "糖尿病合併症-どう対処するか-"岩本安彦(中外医学社). 370 (2002)

    • Related Report
      2003 Annual Research Report
  • [Publications] Soroku Yagihashi: "Diabetic microangiopathy : Pathology and current understanding of its pathogenesis"Verh Dtsch Ges Pathol. 86(1). 91-100 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 八木橋 操六: "糖尿病性神経障害の病理ーここ10年間の新知見を中心にー"日本臨床. 60(suppl 10). 204-208 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Ruichi Wada: "Intracytoplasmic immunoglobulin crystals in follicular lymphoma"Human Pathology. 33(11). 1141-1144 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yoshirou Kitahara: "Decreased blood glucose excursion by nateglinide ameliorated neuropathic changes in Goto-Kakizaki rats an animal model of non-obese type 2 diabetes"Metabolism. 51(11). 1452-1457 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Takashi Imaizumi: "Interferon-gamma stimulates the expression of galectin-9 in cultured human endothelial cells"J Leukoc Biol. 72(3). 486-491 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Hiroyasu Sakuraba: "Reduced beta-cell mass and expression of oxidative stress-related DNA damage in the islet of Japanese Type II diabetic patients"Diabetologia. 45(1). 85-96 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 八木橋操六: "糖尿病合併症ーどう対処するかー"岩本安彦(中外医学社). 370 (2002)

    • Related Report
      2002 Annual Research Report

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Published: 2002-04-01   Modified: 2016-04-21  

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