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2011 Fiscal Year Annual Research Report

低酸素応答転写制御ネットワークの網羅的解析による慢性腎臓病の病態生理の解明

Research Project

Project/Area Number 21390260
Research InstitutionThe University of Tokyo

Principal Investigator

南学 正臣  東京大学, 医学部附属病院, 特任講師 (90311620)

Co-Investigator(Kenkyū-buntansha) 和田 健彦  東京大学, 医学部附属病院, 助教 (90447409)
稲城 玲子  東京大学, 医学部附属病院, 特任研究員 (50232509)
田中 哲洋  東京大学, 保健健康推進本部, 助教 (90508079)
Keywords虚血 / 慢性腎臓病 / 腎不全 / 低酸素
Research Abstract

本研究の目的は低酸素応答という重要な個別生命現象に焦点を絞って転写制御ネットワークの網羅的解析を行い、得られた知見を腎臓病学の病態生理に応用するものである。
前年度から引き続いて行っている培養細胞を用いたChIPシークエンスによるHIFの転写制御ネットワークの研究について、条件設定の最適化を行い、低酸素下でのHIF-1結合遺部位を2060箇所同定した。同時に、低酸素状態においてHIF-1が正常に発現している細胞とHIF-1をノックダウンした細胞におけるmicroarray解析の条件も最適化し、480遺伝子がHIF-1依存性に発現が変化することを見出した。これらに共通する新規HIF-1ターゲット遺伝子であるGeneAについては、GeoProfileにて腎細胞癌における発現の亢進が再現性をもって報告されており、tissue arrayを施行することで腎細胞癌における蛋白レベルでの発現亢進を確認することが出来た。レポーターアッセイを行い、HIF-1のGeneAのintronへの結合が低酸素状態での発現亢進に必須であることを確認した。また、GFPとのfusion proteinを培養細胞に発現させ、GeneAの蛋白産物が細胞質分裂の終期にintercellular bridgeに集まること、低酸素では培養細胞のうち多核細胞が増加すること、GeneAをノックダウンすると多核細胞が更に増えることを見出し、GeneAが低酸素状態での細胞質分裂に重要な役割を果たすことを示した。

  • Research Products

    (16 results)

All 2012 2011

All Journal Article (4 results) (of which Peer Reviewed: 4 results) Presentation (12 results)

  • [Journal Article] Dysregulated oxygen metabolism of the kidney by uremic toxins2012

    • Author(s)
      Chiang CK, Tanaka T, Nangaku M
    • Journal Title

      J Ren Nutr

      Volume: 22 Pages: 77-80

    • URL

      http://www.sciencedirect.com/science/article/pii/S1051227611002184

    • Peer Reviewed
  • [Journal Article] Glyoxalase I retards renal senescence2011

    • Author(s)
      Ikeda Y, Inagi R, Miyata T, Nagai R, Arai M, Miyashita M, Itokawa M, Fujita T, Nangaku M.
    • Journal Title

      Am J Pathol

      Volume: 179 Pages: 2810-21

    • URL

      http://linkinghub.elsevier.com/retrieve/pii/S0002-9440(11)00840-6

    • Peer Reviewed
  • [Journal Article] Indoxyl sulfate, a representative uremic toxin, suppresses erythropoietin production in a HIF-dependent manner2011

    • Author(s)
      Chiang CK, Tanaka T, Inagi R, Fujita T, Nangaku M
    • Journal Title

      Lab Invest

      Volume: 91 Pages: 1564-71

    • DOI

      doi:10.1038/labinvest.2011.114

    • Peer Reviewed
  • [Journal Article] Epigenetic regulation for hypoxic response via HIF and histone demethylase2011

    • Author(s)
      Mimura I, Tanaka T, Wada Y, Kodama T, Nangaku M.
    • Journal Title

      J Pharmacol Sci

      Volume: 115 Pages: 453-8

    • URL

      https://www.jstage.jst.go.jp/article/jphs/advpub/0/advpub_10R19FM/_article

    • Peer Reviewed
  • [Presentation] Abnormal Oxygen Metabolism and Epigenetic changes in Diabetic Kidney Disease2012

    • Author(s)
      Nangaku
    • Organizer
      Keystone Symposium on Complications of Diabetes
    • Place of Presentation
      Boston, U.S.A.(Invited)
    • Year and Date
      2012-03-12
  • [Presentation] Dysregulated oxygen metabolism of the kidney by uremic toxins2011

    • Author(s)
      Nangaku
    • Organizer
      7^<th> International Congress on Uremia Research and Toxicity
    • Place of Presentation
      名古屋(Invited)
    • Year and Date
      20110512-20110514
  • [Presentation] Indoxyl sulfate impairs hypoxia response in cultured proximal tubular cells2011

    • Author(s)
      Tanaka, et al.
    • Organizer
      7^<th> International Congress on Uremia Research and Toxicity
    • Place of Presentation
      名古屋
    • Year and Date
      20110512-20110514
  • [Presentation] Indoxyl sulfate, a representative uremic toxin, suppresses erythropoietin production in HIF-dependent manner2011

    • Author(s)
      Chiang, et al.
    • Organizer
      7^<th> International Congress on Uremia Research and Toxicity
    • Place of Presentation
      名古屋
    • Year and Date
      20110512-20110514
  • [Presentation] Derangement of Oxygen Sensing for Erythropoietin (EPO) Production by Unfolded Protein Response (UPR)2011

    • Author(s)
      Inagi, et al.
    • Organizer
      The 44^<th> Annual Meeting of the American Society of Nephrology
    • Place of Presentation
      Philadelphia, U.S.A.
    • Year and Date
      2011-11-12
  • [Presentation] Indoxyl Sulfate Induces Cbp/p300-Interacting Transactivator, with Glu/Asp-Rich Carboxy-Terminal Domain, 2, and Impairs Hypoxia Response in Proximal Tubular Cells2011

    • Author(s)
      Tanaka, et al.
    • Organizer
      The 44^<th> Annual Meeting of the American Society of Nephrology
    • Place of Presentation
      Philadelphia, U.S.A.
    • Year and Date
      2011-11-12
  • [Presentation] Identification & Characterization of a Novel Oncogenic HIF-1 Target Involved in Renal Cell Carcinoma2011

    • Author(s)
      Shoji, et al.
    • Organizer
      The 44^<th> Annual Meeting of the American Society of Nephrology
    • Place of Presentation
      Philadelphia, U.S.A.
    • Year and Date
      2011-11-12
  • [Presentation] HIF1 Modulates Chromatin Conformational Change by Recruiting KDM3A and Enhances Regulation of Glucose Transporter 3 in Endothelial Cells2011

    • Author(s)
      Mimura, et al.
    • Organizer
      The 44^<th> Annual Meeting of the American Society of Nephrology
    • Place of Presentation
      Philadelphia, U.S.A.
    • Year and Date
      2011-11-11
  • [Presentation] Renal Ischemia Reperfusion Injury Promotes Mid-Term Tubular Senescence2011

    • Author(s)
      Ikeda, et al.
    • Organizer
      The 44^<th> Annual Meeting of the American Society of Nephrology
    • Place of Presentation
      Philadelphia, U.S.A.
    • Year and Date
      2011-11-10
  • [Presentation] Progression of CKD following AKI : Role of hypoxia2011

    • Author(s)
      Nangaku
    • Organizer
      The 44^<th> Annual Meeting of the American Society of Nephrology
    • Place of Presentation
      Philadelphia, U.S.A.(Invited)
    • Year and Date
      2011-11-10
  • [Presentation] Mechanism of the development of renal anemia and its treatment2011

    • Author(s)
      Nangaku
    • Organizer
      International Forum of Chronic Kidney Disease of the Taiwan Society of Nephrology
    • Place of Presentation
      Taipei, Taiwan(Invited)
    • Year and Date
      2011-07-10
  • [Presentation] Cellular Defense Systems in Hypoxia : Mechanisms for Renal Protection2011

    • Author(s)
      Nangaku
    • Organizer
      World Congress of Nephrology
    • Place of Presentation
      Vancouver, Canada(Invited)
    • Year and Date
      2011-04-11

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Published: 2013-06-26  

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