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2008 Fiscal Year Annual Research Report

腎臓における小胞体ストレスの病態生理学的意義の解明

Research Project

Project/Area Number 19590939
Research InstitutionThe University of Tokyo

Principal Investigator

稲城 玲子  The University of Tokyo, 医学部附属病院, 特任研究員 (50232509)

Co-Investigator(Kenkyū-buntansha) 南学 正臣  東京大学, 医学部・附属病院, 講師 (90311620)
和田 健彦  東京大学, 医学部・附属病院, 助教 (90447409)
KeywordsER stress preconditioning / Unfolded protein response / ER chaperone / 翻訳制御 / Thy-1腎炎 / 慢性腎臓病 / 糸球体障害 / 尿細管障害
Research Abstract

申請者らは、昨年度までにネフローゼ(puromycin腎症)、糸球体腎炎(Thy-1腎炎)、急性腎不全、(虚血再潅流)モデルラットにおいて、糸球体、及び尿細管病変部で小胞体ストレスによる細胞応答経路(unfolded protein response: uPR)が著しく亢進していることを明らかにしてきた。そこで本年度は、それら病変部の小胞体ストレスが病態形成・進展に病因として関与すること、さらにそれを標的とした治療戦略の可能性を明らかにする目的で、小胞体ズトセスpreconditioning(腎疾患誘導前に腎障害を及ぼさない少量の小胞体ストレス誘導剤、ツニカマイシンあるいはタプシガルギンを前投与)が腎保護効果を有するか否かを検討した。その結果、小胞体ストレスpreconditioning、つまり腎毒性の無い少量のツツニカマイシンあるいはタブシガルギン投与は腎病理や機能に影響を及ぼさないが、軽度のUPR(GRP78やORP150などの小胞体シャペロン発現亢進やeIF2α,PERKのリン酸を介した翻訳抑制経路の活性化)を誘導した。preconditioning4日後}とThy-1腎炎を誘導すると、未処置の対照群に比し、糸球体病変(mlicroanetirysm、糸封体の癒着や肥大、メサンギウム細胞増殖)や腎機能低下(蛋白尿)が著明に軽減した。その際、preconditioning群では、Thy-1腎炎で誘導される過剰なUPR亢進(小胞体シャペロン発現誘導や翻訳抑制)が著明に抑制されており、小胞体ストレスpreconditioningによるbasal UPRの軽度惹起が糸球体障害に対して保護的に働くことが明らかとなった。これら成果によって、basal UPRの惹起は腎障害時の腎臓構成細胞の小胞体機能維持、ひいては腎保護効果を有することが示され、腎病態進展時に生じる過剰なUPR変動を制御することによる治療効果の可能性が示唆された。

  • Research Products

    (24 results)

All 2009 2008

All Journal Article (10 results) (of which Peer Reviewed: 10 results) Presentation (12 results) Book (2 results)

  • [Journal Article] Endoplasmic reticulum stress in thekidney as a novel mediator of kidney injury.2009

    • Author(s)
      Inagi, R
    • Journal Title

      Nephron Exp Nephrol (In press)

    • Peer Reviewed
  • [Journal Article] Contribution of T lymphocytes to ratrenal ischemia/reperfusion injury.2009

    • Author(s)
      Noiri, E et al.
    • Journal Title

      Clin Exp Nephrol 13

      Pages: 25-32

    • Peer Reviewed
  • [Journal Article] Glyoxalse I overexpression ameliorates renal ischemia-reperfusion injury inrats2009

    • Author(s)
      Kumagai, T et al.
    • Journal Title

      Am J Physiol Renal Physiol 296

      Pages: F912-921

    • Peer Reviewed
  • [Journal Article] Suppression of MAP3 kinase 6 mediates anti-angiogenic and tumor-suppressive effects via VEGF repression.2009

    • Author(s)
      Eto, N et al.
    • Journal Title

      Am J Pathol (in press)

    • Peer Reviewed
  • [Journal Article] Metallothionein is upregulated by hypoxia and stabilizes hypoxia-iducible favtor in the kidney.2009

    • Author(s)
      Kojima, I et al.
    • Journal Title

      Kidney Int 75

      Pages: 268-277

    • Peer Reviewed
  • [Journal Article] Hemoglobin is expressed as anti-oxidant factor by mesangial cell2008

    • Author(s)
      Nishi, H et al.
    • Journal Title

      J Am Soc Nephrol 19

      Pages: 1500-1508`

    • Peer Reviewed
  • [Journal Article] Preconditioning with endoplasmic reticulum stress ameliorates mesangioproliferative glomerulonephritis.2008

    • Author(s)
      Inagi, R et al.
    • Journal Title

      J Am Soc Nephrol 19

      Pages: 915-922

    • Peer Reviewed
  • [Journal Article] Chronic hypoxia aggravates renal injury via suppression of Cu/Zn-SOD-a proteomic analysis.2008

    • Author(s)
      Son, D et al.
    • Journal Title

      Am J Physiol Renal Physiol 294

      Pages: F62-72

    • Peer Reviewed
  • [Journal Article] Albumin suppresses vascular endothelial growth factor via alteration of hypoxia-inducible factor/hypoxia-responsive element pathway.2008

    • Author(s)
      Katavetin, P et al.
    • Journal Title

      Biochem Biophys Res Commun 367

      Pages: 305-310

    • Peer Reviewed
  • [Journal Article] Angiotensin-induced hypoxia the kidney: function and structural change of the renal cirulation.2008

    • Author(s)
      Nangaku, M et al.
    • Journal Title

      Adv Exp Med Biol 121

      Pages: 85-99

    • Peer Reviewed
  • [Presentation] Organ protective effects of tunicamycin as an endoplasmic reticulum stress inducer.2008

    • Author(s)
      Inagi, R
    • Organizer
      World Confrence on Magic Bullts(Ehrlich II)
    • Place of Presentation
      Nurnberg, Germany
    • Year and Date
      20081003-05
  • [Presentation] Glyoxalase I overexpression lowers hypoxia-induced oxidative stress and ameliorates renal ischemia-reperfusion injury in the rat.2008

    • Author(s)
      Inagi, R et al.
    • Organizer
      International Society of Oxygen Trapsport to Tissues
    • Place of Presentation
      Sapporo, Japan
    • Year and Date
      20080803-07
  • [Presentation] Glyoxalase I overexpression lowers oxidative stress and ameliorates renalischemia-reperfusion injury in the rat.2008

    • Author(s)
      Kumagai, R et al.
    • Organizer
      Keystone Symposium
    • Place of Presentation
      Vapcouver, Canada
    • Year and Date
      20080115-20
  • [Presentation] Mircoarray analysis of chronic hypoxic kidney revealed activation of HIF by metallothionein2008

    • Author(s)
      Kojima, I et al.
    • Organizer
      Keystone Symposium
    • Place of Presentation
      Vapcouver, Canada
    • Year and Date
      20080115-20
  • [Presentation] A novel class of prolyl hydroxylase inhibitors induces angriogenesis and exerts organ protection against ischemia.2008

    • Author(s)
      Nangaku, M et al.
    • Organizer
      Keystone Symposium
    • Place of Presentation
      Vapcouver, Canada
    • Year and Date
      20080115-20
  • [Presentation] MAP3 kinase 6 mediates VEGF expression and particpates in tumorigenesis and angiogenesis.2008

    • Author(s)
      Eto, N at al
    • Organizer
      Keystone Symposium
    • Place of Presentation
      Vapcouver, Canada
    • Year and Date
      20080115-20
  • [Presentation] Chronic hypoxia aggravates renal injury via suppression of Cu/Zn-SOD-a proteomic analysis.2008

    • Author(s)
      Son, D et al.
    • Organizer
      Keystone Symposium
    • Place of Presentation
      Vancouver, Canada
    • Year and Date
      20080115-20
  • [Presentation] Transgenic Overexpression of Cytoglobin Improves the Kidney Ischemia/Reperfusion Injury. Via Amelioration of Oxidative Stress.2008

    • Author(s)
      Nishi, H et al.
    • Organizer
      American Society of Nephrology
    • Place of Presentation
      Philadelphia, USA
    • Year and Date
      2008-11-08
  • [Presentation] Endoplasmic Reticulum Stress Induces Autophagy in Renal Proximal Tubular Cells.2008

    • Author(s)
      Kawakami,T et al.
    • Organizer
      American Society of Nephrology
    • Place of Presentation
      Philadelphia, USA
    • Year and Date
      2008-11-06
  • [Presentation] Glyoxalase I Reheves Endoplasmic Reticulum Stress Induced by Rypoxia.2008

    • Author(s)
      Ihagi, R et al.
    • Organizer
      Amnerican Society of Nephrology
    • Place of Presentation
      Philadelphia, USA
    • Year and Date
      2008-11-06
  • [Presentation] Microarray Analysis of Chronic Hypoxic Kidney Revealed Activation of HIF by Metallothionein.2008

    • Author(s)
      Kojima, I et al.
    • Organizer
      American Society of Nephrology
    • Place of Presentation
      Philadelphia, USA
    • Year and Date
      2008-11-06
  • [Presentation] Preconditioning with endoplasmic reticulum stress ameliorates anti-Thylglomerulonephritis in rats.2008

    • Author(s)
      Inagi, R et al.
    • Organizer
      Congress of ERA/EDTA
    • Place of Presentation
      Stockholm, Sweden
    • Year and Date
      2008-05-11
  • [Book] CKDに伴う貧血2009

    • Author(s)
      稲城玲子、南学正臣
    • Publisher
      医薬ジャーナル社(印刷中)
  • [Book] The Maillard reaction Recent Advances in food and biomedical sciences2008

    • Author(s)
      Kumagai, T et al.
    • Total Pages
      337
    • Publisher
      Annals of the New York Academy of Science

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Published: 2010-06-11   Modified: 2016-04-21  

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