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2002 Fiscal Year Final Research Report Summary

Molecular pharmacological study about mechanisms of increased AT1 receptor expression in the brain of spontaneously hypertensive rats

Research Project

Project/Area Number 13672300
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Biological pharmacy
Research InstitutionShowa Pharmaceutical University

Principal Investigator

KUBO Takao  Showa Pharmaceutical University, Department of Pharmaceutical Sciences, Professor, 薬学部, 教授 (10128598)

Project Period (FY) 2001 – 2002
Keywordsangiotensin / receptor / hypertension / central nervous system / hypothalamus / AT1 receptors / gene
Research Abstract

The angiotensin type 1 (AT1) receptor gene is overexpressed in the brain of spontaneously hypertensive rats (SHR) and this overexpression of the receptor is an important causal factor for hypertension in SHR. We examined whether there are mutations responsible for the overexpression of the AT1 receptor gene in SHR AT1 receptor promoter region. Sequence analysis identified one single base mutation unique to the SHR AT1 receptor gene promoter region when compared to that of Wistar Kyoto rats (WKY). Electrophoretic mobility shift assay (EMSA) showed that there were 3 major similar DNA protein complexes against WKY and SHR oligonucleotide. Additionally, the oligonucleotide bearing the SHR sequence produced an extra band. However, promoter/luciferase reporter assay demonstrated that the promoter activity of SHR AT1 receptor promoters (-2050 to +57) was lower than that of WKY. Next, we examined whether changes in the level of the transcriptional factors responsible for AT1 receptor gene expression are involved in the overexpression of the AT1 receptor gene hi SHR brain. EMSA showed that Sp1 and AP2 are increased in nuclear extracts of hypothalamus from SHR. Spl decoy phosphorothioate oligodeoxynucleotides injected into the lateral ventricle produced a decreased in blood pressure in SHR. The findings suggest that Sp1 and AP2 levels are increased in the hypothalamus of SHR. These change in Sp1 an AP2 might be involved in developmen of hypertension in SHR.

  • Research Products

    (8 results)

All Other

All Publications (8 results)

  • [Publications] Takao Kubo et al.: "Renin antisense injected intraventricularly decreases blood pressure in spontaneously hypertensive rats"Brain Research Bulletin. 56. 23-28 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Takao Kubo et al.: "Angiotensin receptor blockade in the anterior hypothalamic area inhibits stress-induced pressor responses in rats"Brain Research Bulletin. 56. 569-574 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Takao Kubo et al.: "Activation of hypothalamic angiotensin receptors produces pressor responses via cholinergic inputs to the rostral ventrolateral medulla in normotensive and hypertensive rats"Brain Research. 953. 232-245 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Tosie Kambe et al.: "Existence of a mutation of angiotensin AT1 receptor gene promoter region involved in inhibition of AT1 receptor gene transcription in spontaneously hypertensive rats"Hypertension Research. 26. 245-250 (2003)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Takao Kubo, Atsushi Ikezawa, Toshie Kambe, Yukihiko Hagiwara, Ryuji Fukumori: "Renin antisense injected intraventricularly decreases blood pressure in spontaneously hypertensive rats."Brain Research Bulletin. 56 (1). 23-28 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Takao Kubo, Hiroyuki Numakura, Shuji Endo, Yukuhiko Hagiwara, Ryuji Fukumori: "Angiotensin receptor blockade in the anterior hypothalamic area inhibits stress-induced pressor responses in rats."Brain Research Bulletin. 56 (6). 569-574 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Takao Kubo, Yukihiko Hagiwara, Shuji Endo, Ryuji Fukumori: "Activation of hypothalamic angiotensin receptors produces pressor responses via cholinergic inputs to the rostral ventrolateral medulla in normotensive and hypertensiv rats."Brain Research. 953 (3). 232-245 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Toshie Kambe, Hitoshi Hiruki, Takao Kubo: "Existence of a mutation of Angiotensin AT1 receptor gene promoter region involved in inhibition of AT1 receptor gene transcription in spontaneously hypertensive rats."Hypertension Research. 26 (3). 245-250 (2003)

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2004-04-14  

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