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Creation and analysis of transgenic and knockout animals in hypertension and its related diseases.

Research Project

Project/Area Number 08556055
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section展開研究
Research Field Applied molecular and cellular biology
Research InstitutionUNIVERSITY OF TSUKUBA

Principal Investigator

MURAKAMI Kazuo  University of Tsukuba, Institute of Applied Biochemistry, Professor, 応用生物化学系, 教授 (70110517)

Co-Investigator(Kenkyū-buntansha) NOMURA Tatsuji  Laboratory Animal Research Center, Director, 所長 (10072399)
FUKAMIZU Akiyoshi  University of Tsukuba, Institute of Applied Biochemistry, Associate Prof., 応用生物化学系, 助教授 (60199172)
MIYAZAKI Hitoshi  University of Tsukuba, Institute of Applied Biochemistry, Associate Prof., 応用生物化学系, 助教授 (40183636)
杉山 文博  筑波大学, 基礎医学系, 講師 (90226481)
Project Period (FY) 1996 – 1998
Project Status Completed (Fiscal Year 1998)
Budget Amount *help
¥18,000,000 (Direct Cost: ¥18,000,000)
Fiscal Year 1998: ¥4,200,000 (Direct Cost: ¥4,200,000)
Fiscal Year 1997: ¥5,000,000 (Direct Cost: ¥5,000,000)
Fiscal Year 1996: ¥8,800,000 (Direct Cost: ¥8,800,000)
Keywordsknock out mouse / angiotensinogen / cerebellum / angiotensin II receptors / renin-angiotensin system / transgenic mouse / apoptosis / Hippocampus / アンギオテンシンII / アンギオテンシンIV / アンジオテンシノーゲン / 遺伝子欠損マウスス / ホモ欠損マウス / ヘテロ欠損マウス / アルドステロン / つくば高血圧マウス / トランスジェニックマウス / 心肥大 / トランスジェニックラット
Research Abstract

The important research results in this project are summarized in the folowing two sections.
1) Functional analysis of angiotensinogen-knockout mice
Genetically altered mice lacking angiotensinogen (Agt-KO) showed an expected phenotype, such as marked hypotension, but unexpected ones including abnormal kidney morphology, reduced survival rates of newborns, and impaired blood-brain barrier function after cold injury. To examine whether disruption of the angiotensinogen gene is responsible for the observed phenotypes, we generated a line of mice heterozygous for the mouse angiotensinogen gene under the control of a mouse metallothionein-I promoter(MT-Agt) and crossmated transgenic mice with Agt-KO mice. The resulting mic (MT-Agt(+/-)/Agt(-/-) : MT-Agt/KO) produced the plasma level of angiotensin I comparable to that of wild-type mice, and the mutant phenotypes were rescued.
2) New function of angiotensinogen knock-out mice
The morphological analysis in a congenic line of angiotensinogen knock-out mice (Ag-KO) revealed the decreased density in granular layer cells of hippocampus and cerebellum, suggesting neuronal cell of Ag-KO susceptible to apoptotic cell death. This phenomenon was further studied by culture of the hippocampal neurons with decreased concentration of serum. Ag-KO neuronal cells, which showed apoptosis by lower concentration of the serum within several hours, however, survived much longer in the presence of angiotensin II (All) and IV(AIV). This anti-apoptotic action was not interfered by AII receptor antagonists. These results suggest that the renin-angiotensin system could play a critical role in central nervous system, preventing neuronal cells from apoptosis not only by All but also AIV.

Report

(4 results)
  • 1998 Annual Research Report   Final Research Report Summary
  • 1997 Annual Research Report
  • 1996 Annual Research Report
  • Research Products

    (40 results)

All Other

All Publications (40 results)

  • [Publications] R.Morishita et al.: "Role of transcriptional cis-elements,angiotensinogen gene-activating elements,of angiotensinogen gene in blood pressure regulation." Hypertension. 27. 502-507 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] K.Tamura et al.: "Tissue-specific regulation of angiotensinogen gene expression in spontaneously hypertensive rats." Hypertension. 27. 1216-1223 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] K.Yanai et al.: "A cis-acting DNA element located between TATA box and transcription initiation site is critical in response to regulatory sequences in human angiotensinogen gene." J.Biol.Chem.271. 15981-15986 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] K.Murakami et al.: "Hypertensive and hypotensive mice produced by the introduction and disruption of genes on the renin-angiotensin system." Blood Pressure. 5. 36-40 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] E.Takimoto et al.: "Hypertension induced in pregnant mice by placental renin and maternal angiotensinogen." Science. 274. 995-998 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Y.Watanabe et al.: "Chromosomal mapping of human angiotensinogen gene and human renin gene by fluorescence in situ hybridization (FISH) in transgenic mice." Exp.Anim.,. 45. 265-269 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] N.Shiota et al.: "Activation of angiotensin II-forming chymase in the cardiomyopathic hamster heart." J.Hypertension. 15. 431-440 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] F.Sugiyama et al.: "Acceleration of atherosclerotic lesions in transgenic mice with hypertension by the activated renin-angiotensin system." Laboratory Investigation. 76. 835-842 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] K.Yanai et al.: "ATF-like element contributes to hepatic activation of human angiotensinogen promoter." Biochm.Biophys.Res.Commun.237. 158-162 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] T.Tamura et al.: "A novel proximal element mediates the regulation of mouse Ren-1C promoter by retinoblatoma protein in cultured cells." J.Biol.Chem.272. 16845-16851 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Y.Kakinuma et al.: "Anti-apoptotic action of angiotensin fragments to neuronal cells from angiotensinogen knock out mice." Neuroscience Letters. 232. 167-170 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Y.sumida et al.: "Increased cardiac angiotensin II receptors in angiotensinogen deficient mice." Hypertension. 31. 45-49 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Y.Kakinuma et al.: "Impaired blood-brain barrier function in angiotensinogen-deficient mice." Nature Medaicine. 4. 1076-1080 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] J.Ishida et al.: "Rescue of angiotensinogen-knockout mice." Biochem.Biopys.Res.Commun.252. 610-616 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] R.Morishita et al.: "Role of transcriptional cis-elements, angiotensinogen gene-activating elements, of angiotensinogen gene in blood pressure regulation." Hypertension. 27. 502-507 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] K.Tamura et al.: "Tissue-specific regulation of angiotensinogen gene expression in spontaneously hypertensive rats." Hypertension. 27. 1216-1223 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] K.Yanai et al.: "A cis-acting DNA element located between TATA box and transcription initiation site is critical in response to regulatory sequences in human angiotensinogen gene." J.Biol.Chem.271. 15981-15986 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] K.Murakami et al.: "Hypertensive and hypotensive mice produced by the introduction and disruption of genes on the renin-angiotensin system." Blood Pressure. 5. 36-40 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] E.Takimoto et al.: "Hypertension induced in pregnant mice by placental renin and maternal angiotensinogen." Science. 274. 995-998 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Y.Watanabe et al.: "Chromosomal mapping of human angiotensinogen gene and human renin gene by fluorescence in situ hybridization (FISH) in transgenic mice." Exp.Anim.45. 265-269 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] N.Shiota et al.: "Activation of angiotensin II-forming chymase in the cardiomyopathic hamster heart." J.Hypertension. 15. 431-440 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] F.Sugiyama et al.: "Acceleratioon of atherosclerotic lesions in transgenic mice with hypertension by the activated renin-angioten system." Laboratory Investigation. 76. 835-842 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] K.Yanai et al.: "ATF-like element contributes to hepatic activation of human angiotensinogen promoter." Biochem.Biophys.Res.commu.237. 158-162 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] T.Tamura et al.: "A novel proximal element mediates the regulation of mouse Ren-1C promoter by retinoblastoma protein in cultured cells." J.Biol.Chem.272. 16845-16851 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Y.Kakinuma et al.: "Anti-apoptotic action of angiotensin fragments to neuronal cells from angiotensinogen knock-out mice." Neuroscience Letters. 232. 167-170 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Y.Sumida et al.: "Increased cardiac angiotensin II receptors in angiotensinogen deficient mice." Hypertension. 31. 45-49 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Y.Kakinuma et al.: "Impaired blood-brain barrier function in angiotensinogen-deficient mice." Nature Medicine. 4. 1076-1080 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] J.Ishida et al.: "Rescue of angiotensinogen-knockout mice." Biochem.Biophys.Res.commun.252. 610-616 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] K.Tamura et al.: "A novel proximal element mediates the regulation of mouse Ren-1C promoter by retinoblastoma protein in cultured cells." J.Biol.Chem.272. 16845-16851 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] Y.Kakinuma et al.: "Anti-apoptotic action of angiotensin fragments to neuronal cells from angiotensinogen knock-out mice." Neuroscience Letters. 232. 167-170 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] Y.sumida et al.: "Increased cardiac angiotensin II receptors in angiotensinogen-deficient mice." Hypertension. 31. 45-49 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Y.kaminuma et al.: "Impaired blood-brain barrier function in angiotensinogen-deficient mice" Nature Mediciene. 4. 1076-1080 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] J.Ishida et al.: "Rescue of angiotensinogen-knockout mice." Miochem.Biophys.Res.Commun.252. 610-616 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] N.Shiota et al.: "Activation of angiotensin II-forming chymase in the cardiomyopathic hamster heart." J.Hypertension. 15. 431-440 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] F.Sugiyama et al.: "Acceleration of atherosclerotic lesions in transgenic mice with hypertensin by the activated renin-angiotension system." Laboratory Investigation. 76. 835-842 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] K.Yanai et al.: "ATF-like element contributes to hepatic activation of human angiotensinogen promoter." Biochem.Biophys.Res.Commun.237. 158-162 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] R.Morishita et al.: "Role of transcriptional cis-elements,angiotensinogen gene-activatiing elements,of angiotensinogen gene in blood pressure regulation." Hypertension. 27. 502-507 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] K.Tamura et al.: "Tissue-specific regulation of angiotensinogen gene experssion in spontaneously hypertensive rats." Hypertension. 27. 1216-1223 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] K.Yanai et al.: "A cis-acting DNA element located between TATA box and transcription initiation site is critical in response to regulatory sequences in human angiotensinogen gene." J.Biol.Chem.271. 15981-15986 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] K.Murakami et al.: "Hypertensive and hypotensive mice produced by the introduction and disruption of genes on the renin-angiotensin system." Blood Pressure. 5. 36-40 (1996)

    • Related Report
      1996 Annual Research Report

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Published: 1996-04-01   Modified: 2016-04-21  

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