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STUDIES ON THE KALLIKREIN-KININ SYSTEM : ANALYSIS USING THE GENETICALLY KININOGEN-DEFICIENT RATS

Research Project

Project/Area Number 04454534
Research Category

Grant-in-Aid for General Scientific Research (B)

Allocation TypeSingle-year Grants
Research Field Biological pharmacy
Research InstitutionKITASATO UNIVERSITY

Principal Investigator

OH-ISHI Sachiko  KITASATO UNIV., SCH.PHARM.SCI., PROFESSOR, 薬学部, 教授 (70050416)

Co-Investigator(Kenkyū-buntansha) UTSUNOMIYA Iku  KITASATO UNIV., SCH.PHARM.SCI., ASSISTANT PROFESSOR, 薬学部, 助手 (70168722)
YAMAKI Kohji  KITASATO UNIV., SCH.PHARM.SCI., ASSISTANT PROFESSOR, 薬学部, 助手 (70174597)
HAYASHI Izumi  KITASATO UNIV., SCH.PHARM.SCI., LECTURER, 薬学部, 講師 (90172999)
UENO Akinori  KITASATO UNIV., SCH.PHARM.SCI., ASSOCIATE PROFESSOR, 薬学部, 助教授 (00112657)
三田 征治  北里大学, 薬学部, 助手 (90200039)
Project Period (FY) 1992 – 1994
Project Status Completed (Fiscal Year 1994)
Budget Amount *help
¥6,600,000 (Direct Cost: ¥6,600,000)
Fiscal Year 1994: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 1993: ¥2,400,000 (Direct Cost: ¥2,400,000)
Fiscal Year 1992: ¥2,900,000 (Direct Cost: ¥2,900,000)
KeywordsKININOGEN / KININOGEN-DEFICIENT RAT / A POINT MUTATION / SECRETION DEFECT / HIGH MOLECULAR WEIGHT KININOGEN / LLOW MOLECULAR WEIGHT KININOGEN / BRADYKININ / 一アミノ酸変異 / 尿キニン / B / N・KatholieK rat / カリクレイン・キニン系 / ブラウン・ノルウェイ・ラット / カラゲニン胸膜炎 / ワンポイントミューテーション / Brown Norway rat / 高血圧 / エンドトキシン / ブラジキニン・アンタゴニスト / 血管透過性亢進
Research Abstract

1.Secretion defect of kininogens by the liver of B/N-Katholiek rats : Primary cultures of the hepatocytes of kininogen-deficient B/N-Katholiek and normal B/N-Kitasato rats were examined for synthesis and secretion of HMW-kininogen (HK) and LMW-Kininogen (LK) by the assessment of the incorporation of [^<35>S] -methionine. Hepatocytes of both strains of rats synthesized HK and LK similarly. Hepatocyte cultures of normal rats secreted HK and LK into the medium in 2 to 3 hrs, but cultures of kininogen-deficient rats did not secrete and retained HK and LK in the cells, which localized in the lysosomal fraction.
2.Cloning of HK cDNA of B/N-Katholiek and B/N-Kitasato rats : By an analysis of the sequence of the HK cDNA of B/N-Katholiek and B/N-Kitasato rats we found a point mutation of G to A at nucleotide 487, which locates at the heavy chain region of HK and LK.The mutation results in an amino acid transposition of alanine 163 to threonine. When a plasmid constructed with the nucleotide fragment containing G to A transition transfected into COS-1 cells , HK hardly secreted into the medium in 24 hr incubation. On the contrast, the cells transfected with the plasmide containing normal nucleotide sequence could release HK.Therefore the result suggests that a point mutation of alanine to threonine could be a cause of secretion defect of B/N-Katholiek strain.
3.Role of HK and LK in the body : By the experiment using Western blot analysis, HK molecule that had been released bradykinin, i.e. kinin-free HK,was detected in the pleural exudate of rat carrageenin pleurisy. The result indicates that at the inflammatory site kinin may be released from HK to act as an inflammatory mediator. On the other hand urinary kinin could be derived from plasma LK,because urinary kinin content in kininogen-deficient B/N-Katholiek rats increased more significantly when infused with LK than HK.

Report

(4 results)
  • 1994 Annual Research Report   Final Research Report Summary
  • 1993 Annual Research Report
  • 1992 Annual Research Report

Research Products

(30 results)

All Other

All Publications (30 results)

  • [Publications] Hayashi,l.,Hoshiko,S.,Makabe,O.and Ohishi,S.: "A point mutation of ala・nine 163 to threonine is responsible for the defective secretion of high molecular weight kininogen by the liver of Brown Norway Katholiek rats." J.Biol.Chem.,. 268. 17219-17224 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Hayashi,I.and Oh-ishi,S.: "Plasma kininogen deficiency:Associated defective secretion of kininogens by primary cultures of hepatocytes from Brown Norway Katholiek rats." J.Biochem.(Tokyo). 113. 531-537 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Fujie,H.,Hayashi,I.and Oh-ishi,S.20GB03:The kinin release from high molecular weight-kininogen is responsible for inflammatory exudation in rats: Life Sci.53. 1691-1701 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Mimura,T.,Hayashi,I.,Hoshino,T.and Oh-ishi,S.: "Demonstration of high molecular-weight kininogen in kininogen-deficient ratkidneys." J.Biochem.(Tokyo),. 116. 59-63 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Hagiwara,Y.,Kojima,M.,Hayashi,I.and Oh-ishi,S.: "Demonstration of derivation of rat urinary bradykinin from plasma low-molecular-weight kininogen:A study using kininogen-deficient rats." Biochem.Biophys.Res.Commun.204. 1219-1224 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Tokumasu,T.,Ueno,A.and Oh-ishi,S.20GB06:A hypotensive response induced by des-Arg^9-bradykinin in young Brown/Norway rats pretreated with endotoxin.21GC06:Eur.J.Pharmacol.: 274. 225-228 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] 分担:大石幸子(P11〜17,136〜150)上野晃憲(P.213〜221)林泉(P.168〜176): "キニンとアンギオテンシン" 講談社サイエンティフィク, 278 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Hayashi, I., Fujii, H., Mita, M.and Oh-ishi, S.: "Characterization of the heredity of kininogen deficiency in Brown Norway Katholiek strain rats." Life Sci.51. 135-142 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Oh-ishi, S., Hayashi, I., Yamaki, K.and Utsunomiya, I.: "Kininogen deficiency in the rat." Agent.Action.38/I. 277-291 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Hayashi, I., and Oh-ishi, S.: "Plasma kininogen deficiency : Associated defective secretion of kininogens by primary cultures of hepatocytes from Brown Norway Katholiek rats." J.Biochem.(Tokyo). 113. 531-537 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Hayashi, I., Hoshiko, S., Makabe, O.and Ohishi, S.: "A point mutation of alanine 163 to threonine is responsible for the defective secretion of high molecular weight kininogen by the liver of Brown Norway Katholiek rats." J.Biol.Chem.268. 17219-17224 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Fujii, H., Hayashi, I.and Oh-ishi, S.: "The kinin release from high molecular weight-kininogen is responsible for inflammatory exudation in rats" Life Sci.53. 1691-1701 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Mimura, T., Hayashi, I., Hoshino, T.and Oh-ishi, S.: "Demonstration odf high-molecular-weight kininogen in kininogen-deficient rat Kidneys." J.Biochem., (Tokyo). 116. 59-63 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Hagiwara, Y., Kojima, M., Hayashi, I.and Oh-ishi, S.: "Demonstration of derivation of rat urinary brady-kinin from plasma low-molecular-weight kininogen." Biochem.Biophys.Res.Commun.204. 1219-1224 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Tokumasu, T., Ueno, A.and Oh-ishi, S.: "A hypotensive response induced by des-Arg^9-bradykinin in young Brown-Norway rats pretreated with endotoxin." Eur.J.Pharmacol.274. 225-228 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Hayashi,I.,Hoshiko,S.,Makabe,O.and Ohishi,S.: "A point mutation of ala nine 163 to threonine is responsible for the defective secretion of high molecular weight kininogen" J.Biol.Chem.,. 268. 17219-17224 (1993)

    • Related Report
      1994 Annual Research Report
  • [Publications] Hayashi,I.and Oh-ishi,S.: "Plasma kininogen deficiency:Associated defec tive secretion" J.Biochem.(Tokyo). 113. 531-537 (1993)

    • Related Report
      1994 Annual Research Report
  • [Publications] Fujie,H.,Hayashi,I.and Oh-ishi,S.: "The kinin release from high molecular weight-kininogen" Life Sci.53. 1691-1701 (1993)

    • Related Report
      1994 Annual Research Report
  • [Publications] Mimura,T.,Hayashi,I.,Hoshino,T.and Oh-ishi,S.: "Demonstration of high molecular-weight kininogen in kininogen-deficient ratkidneys." J.Biochem.(Tokyo).116. 59-63 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Hagiwara,Y.,Kojima,M.,Hayashi,I.and Oh-ishi,S.: "Demonstration of derivation of rat urinary bradykinin trom plasma low-molecular-weight kininogen." Biochem.Biophys.Res.Commun.204. 1219-1224 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Tokumasu,T.,Ueno,A.and Oh-ishi,S.: "A hypotensive response induced by des-Arg^9-bradykinin" Eur.J.Pharmacol.274. 225-228 (1995)

    • Related Report
      1994 Annual Research Report
  • [Publications] 大石幸子・上野晃憲、林泉(分担): "キニンとアンギオテンシン" 講談社サイエンティフィク, 278 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] I.Hayashi & S.Oh-ishi: "Plasma Kininogen deficiency:Associated defective secretion of kininogens by primary cultures of hepatocytes from Brown Norway Katholiek rats" Journal of Biochemistry. 113. 531-537 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Izumi Hayashi et al.: "A point mutation of alanine 163 to threonine is reponsible for the defective secretion of high molecular weight kininogen by the liber of Brown Norway Katholiek rats" Journal of Biological Chemistry. 268. 17219-17224 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Hiroshi Fujie et al.: "The kinin release from high molecular weight-kininogen is responsible for inflammatory exudation in rats:Detection of kinin-free-kininogen in the exudate by immunoblot analysis" Life Sciences. 53. 1691-1701 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] I.Utsunomiya et al.: "Differential effects of indomethacin and dexamethasone on cytokine production in carrageenin-induced rat pleurisy" European Journal of Pharmacology. 252. 213-218 (1994)

    • Related Report
      1993 Annual Research Report
  • [Publications] 大石幸子: "キニンとアンギオテンシン 生体調節の分子機構" 講談社サイエンティフィク, 278 (1994)

    • Related Report
      1993 Annual Research Report
  • [Publications] I.Hayashi,H.Fujii,M.Mita and S.Oh-ishi: "Characterization of the heredity of Kininogen deficiency in Broun Norway Katholiek strain rats" Life Sciences. 51. 135-142 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] I.Hayashi and S.Oh-ishi: "Plasma Kininogen deficiency… Associated defective secretion of Kininogens by primary cultures of hepatocytes from Brown Norway Katholiek rats" J.Biochemistry(Tokyo). 113. (5)- (1993)

    • Related Report
      1992 Annual Research Report
  • [Publications] T.Hoshino,I.Hayashi and S.Oh-ishi: "Presence of high molecular weight-Kininogen in rat Kidney and leukocytes" Japanese Journal of Pharmacology. 58. 415- (1992)

    • Related Report
      1992 Annual Research Report

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Published: 1992-03-31   Modified: 2016-04-21  

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