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Physiological function of ageing suppression gene klotho and its role in development of adult disease

Research Project

Project/Area Number 09470159
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Circulatory organs internal medicine
Research InstitutionGunma University

Principal Investigator

NAGAI Ryozo  Gunma University School of Medicine, 2nd Dept of Int Med, Professor, 医学部, 教授 (60207975)

Co-Investigator(Kenkyū-buntansha) UTSUGI Toshihiro  Gunma University School of Medicine, 2nd Dept of Int Med, Assistant, 医学部, 教務員 (10282386)
ARAI Masashi  Gunma University School of Medicine, 2nd Dept of Int Med, Assistant, 医学部, 助手 (60270857)
NAKAMURA Tetsuya  Gunma University School of Medicine, 2nd Dept of Int Med, Assistant Professor, 医学部, 講師 (10272238)
KURABAYASHI Masahiko  Gunma University School of Medicine, 2nd Dept of Int Med, Associate Professor, 医学部, 助教授 (00215047)
NABESHIMA Yo-ichi  Kyoto University, Faculties & Graduated School of Medicine, Dept of Pathology, P, 大学院・研究科, 教授 (60108024)
Project Period (FY) 1997 – 1998
Project Status Completed (Fiscal Year 1998)
Budget Amount *help
¥15,200,000 (Direct Cost: ¥15,200,000)
Fiscal Year 1998: ¥4,900,000 (Direct Cost: ¥4,900,000)
Fiscal Year 1997: ¥10,300,000 (Direct Cost: ¥10,300,000)
KeywordsAGING / ENDOTHELIUM / NITRIC OXIDE / PARABIOSIS / HUMORAL FACTOR / HYPERTENSION / KLOTHO / 動脈硬化 / 腎不全 / 高血圧 / 老化抑制遺伝子 / aging / klotho
Research Abstract

Arteriosclerosis caused by aging is recognized to be a crucial risk factor of cardiovascular disease. We recently established Klotho mouse which causes age-related disorders including arteriosclerosis. However, no information on endothelial function of Klotho mouse or the pathophysiological role of klotho gene product as a circulating factor is available. We demonstrate that the vasodilator response of aorta and arterioles to acetylcholine was significantly attenuated in homozygous klotho mice as compared with wild-type mice. Parabiosis between wild-type and heterozygous klotho mice resulted in restoration of endothelial function in heterozygous Klotho mice. Nitric oxide metabolites (NO2- and NO3-) in urine are significantly lower in heterozygous Klotho mice (142 *16nmol/day) than wild-type mice (241* 28nmol/day). We also showed that kiotho mRNA expression is significantly decreased in spontaneously hypertensive rats, deoxycorticosterone acetate (DOCA) salt hypertensive rats and Otsuka Long-Evans Tokushima Fatty (OLETF) rats developing hypertension, obesity, insulin resistance, and hypertriglyceridemia.
We conclude that the Klotho protein protects against the cardiovascular dysfunction through endothelium-derived NO production by humoral pathways.

Report

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

    (21 results)

All Other

All Publications (21 results)

  • [Publications] Kuro-o M.et al: "Mutation of the mouse Klotho gene leads to a syndrome resembling aging." Nature. 390・6655. 45-51 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Matsumura Y.et al: "Identification of the human Klotho gene and its two transcripts encoding membrane and secreted Klotho protein." Biochem.Byophys.Res.Commun.243・3. 626-630 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Shiraki-Iida T.et al: "Structure of the mouse Klotho gene and its two transcripts encoding membrane and secreted protein." FEBS Lett.424・1-2. 6-10 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Saito Y.et al: "Klotho protein protects against endothelial dysfunction." Biochem.Biophys.Res.Commun.248・2. 324-329 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Aizawa H.et al: "Downregulation of the Klotho gene in the kidney under sustained circulatory stress in rats." Biochem.Biophys.Res.Commun.249・3. 865-871 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Ohyama Y.et al: "Molecular cloning of rat Klotho cDNA : markedly decreased expression of Klotho by acute inflammatory stress." Biochem.Biophys.Res.Commun.251・3. 920-925 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kuro-o M,Matsumura Y,Aizawa H,Kawaguchi h, Suga T,Utsugi T,Ohyama Y,Kurabayashi M,Kaname T,Kume E,Iwasaki H,Iida A,Shiraki-Iida T,Nishikawa S,Nagai R, Nabeshima Y.: "Mutation of the mouse Klotho gene leads to a syndrome resembling ageing." Nature.390(6655). 45-51 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Matsumura Y,Aizawa H,Shiraki-Iida T,Nagai R,Kuro-o M,Nabeshima Y.: "Identification of the human Klotho gene and its transcripts encoding membrane and secreted Klotho protein" Biochem Biophys Res Comm. 242(3). 626-630 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Shiraki-Iida T,Aizawa H,Matsumura Y,Sekine S,Iida A,Anazawa H,Nagai R,Kuro-o M,Nabeshima Y.: "Structure of the mouse Klotho gene and its two transcripts encoding membrane and secreted protein." FEBS Lett.424(1-2). 6-10 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Saito Y,Yamagishi T,Nakamura T,Ohyama Y,Aizawa H,Suga T,Matsumura Y,Masuda H,Kurabayashi M,Kuro-o M,Nabeshima Y,Nagai R.: "Klotho protein protects ageinst endothelial dysfunction." Biochem Biophys Res Commun. 248(2). 324-329 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Aizawa H,Saito Y,Nakamura T,Inoue M,Imanari T,Ohyama Y,Matsumura Y,Masuda H,Oba S,Mise N,Kimura K,Hasegawa A,Kurabayashi M,Kuro-o M,Nabeshima Y,Nagai R.: "Downregulation of the Klotho gene in the kidney under sustained circulatory stress in rats." Biochem Biophys Res Commun. 249(3). 865-871 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Ohyama Y,Kurabayashi M,Masuda H,Nakamura T,Aihara Y,Kaname T,Suga T,Arai M,Aizawa H,Matsumura Y,Kuro-o M,Nabeshima Y,Nagai R: "Molecular cloning of rat klotho cDNA : markedly decreased expression of klotho by acute inflammatory stress." Biochem Biophys Res Comm. 251(3). 920-925 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Saito Y et al: "Klotho protein prorects against endothelial dysfunction." Biochem.Biophys.Res.Commun.248. 324-329 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Aizawa H et al: "Downregulation of the Klotho gene in the kidney under sustained circulatory stress in rats." Biochem.Biophys.Res.Commun.249. 865-871 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Oyama Y et al: "Molecular Cloning of Rat klotho cDNA:Markedly Decreased Expression of klotho by Acute Inflammatory Stress." Biochem.Biophys.Res.Commun.251. 920-925 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Manabe I.et.al.: "Isolation of the embryonic form of smooth muscle myosin heavy chain gene and characterization of its 5'-flanking region" Biochem Biophys Res Commun. 239. 598-605 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Kuro-o M.et.al.: "mutation of the mouse Klotho gene leads to a syndrome resembling ageing" Nature. 390. 45-51 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Suzuki.T et.al.: "A novel biochemical method for aortic dissection" Circulatin. 93. 1244-1249 (1996)

    • Related Report
      1997 Annual Research Report
  • [Publications] Suzuki T.et.al.: "Preferential differentiation of P19 mouse embryonal carenma cells into smooth muscle cells" Circ.Res. 78. 395-404 (1996)

    • Related Report
      1997 Annual Research Report
  • [Publications] Kanda T.et.al.: "Modification of viral myocacditis in mice by interleukin-6" Circ.Res. 78. 848-856 (1996)

    • Related Report
      1997 Annual Research Report
  • [Publications] Watanabe M.et.al.: "Structure and characterization of the 5'-flanking region of the mouse smooth muscle myosin heavy ehain SM 1/2 gene" Circ.Res. 78. 978-989 (1996)

    • Related Report
      1997 Annual Research Report

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Published: 1997-04-01   Modified: 2016-04-21  

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