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The implication of ATP2B1 gene in blood pressure regulation and Ca homeostasis

Research Project

Project/Area Number 16K09648
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Kidney internal medicine
Research InstitutionYokohama City University

Principal Investigator

Hirawa Nobuhito  横浜市立大学, 附属市民総合医療センター, 准教授 (20315766)

Co-Investigator(Kenkyū-buntansha) 谷津 圭介  横浜市立大学, 医学研究科, 客員研究員 (10457856)
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥520,000 (Direct Cost: ¥400,000、Indirect Cost: ¥120,000)
Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2016: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
KeywordsATP2B1 / 高血圧 / カルシウムチャネル / 副甲状腺ホルモン / Ca拮抗薬 / Ca代謝 / 一酸化窒素 / カルシウム / ノックアウト / 降圧メカニズム / トランスジェニック / 血管収縮
Outline of Final Research Achievements

The ATP2B1 gene is associated with hypertension. The ATP2B1 gene encodes plasma membrane calcium ATPase 1 (PMCA1), which has been thought to regulate only intracellular Ca(2+) concentration. We examined the alterations of calcium related factors in systemic heater ATP2B1 knock-out [ATP2B1(+/-)] mice. ATP2B1(+/-) mice exhibited hypocalcemia. The expression of ATP2B1 in the kidney and small intestine decreased, and hypercalciuria was confirmed in ATP2B1(+/-) mice. The intact-PTH levels were lower, and bone mineral density was increased in these mice. These results suggest that hypocalcemia is mainly a result of inhibited bone resorption without compensation by PTH secretion in the case of ATP2B1 knockout. Moreover, NO production may be affected by reduced PTH secretion, which may cause the increase in vascular contractility in these mice. The ATP2B1 gene is important for not only intra-cellular calcium regulation but also for calcium homeostasis and blood pressure control.

Academic Significance and Societal Importance of the Research Achievements

高血圧は、脳心血管病の最大のリスク因子である。中壮年者の血圧を120/80mmHg未満にコントロールされれば、脳心血管病の死亡は、60%抑制することができると考えられている。このような国民病である高血圧を制圧することができれば、国民が元気に長生きできる可能性が高まる。そこで、本研究では、高血圧を制圧するために、血圧の上昇するメカニズム、最適な降圧治療を明らかにするために、高血圧関連遺伝子ATP2B1の意義を明らかにした。本遺伝子は血管の収縮性に関連することが明らかとなり、降圧治療のテーラーメイド医療に有用であることが示唆された。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (8 results)

All 2018 2017 2016

All Journal Article (3 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 3 results,  Open Access: 3 results) Presentation (5 results) (of which Int'l Joint Research: 2 results)

  • [Journal Article] Reduced secretion of parathyroid hormone and hypocalcemia in systemic heterozygous ATP2B1-null hypertensive mice2018

    • Author(s)
      Ehara Yosuke、Hirawa Nobuhito、Sumida Kouichiro、Fujiwara Akira、Kagimoto Minako、Ooki-Okuyama Yuki、Fujita Megumi、Katsumata Mari、Kobayashi Yusuke、Saka Sanae、Katou Ikuma、Yatsu Keisuke、Umemura Satoshi、Tamura Kouichi
    • Journal Title

      Hypertension Research

      Volume: 41 Issue: 9 Pages: 699-707

    • DOI

      10.1038/s41440-018-0067-8

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The effects of anti-hypertensive drugs and the mechanism of hypertension in vascular smooth muscle cell-specific ATP2B1 knockout mice.2018

    • Author(s)
      Okuyama Y, Hirawa N, Fujita M, Fujiwara A, Ehara Y, Yatsu K, Sumida K, Kagimoto M, Katsumata M, Kobayashi Y, Saka S, Umemura S, Tamura K.
    • Journal Title

      Hypertens Res.

      Volume: 41(2) Issue: 2 Pages: 80-87

    • DOI

      10.1038/hr.2017.92

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Enhancement of intrarenal plasma membrane calcium pump isoform 1 expression in chronic angiotensin II-infused mice2017

    • Author(s)
      Wakui Hiromichi、Sumida Koichiro、Fujita Megumi、Ohtomo Yuta、Ohsawa Masato、Kobayashi Ryu、Uneda Kazushi、Azushima Kengo、Haruhara Kotaro、Yatsu Keisuke、Hirawa Nobuhito、Minegishi Shintaro、Ishigami Tomoaki、Umemura Satoshi、Tamura Kouichi
    • Journal Title

      Physiological Reports

      Volume: 5 Issue: 11 Pages: e13316-e13316

    • DOI

      10.14814/phy2.13316

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] 血管平滑筋特異的ATP2B1ノックアウトマウスにおける 高血圧のメカニズムと降圧薬の効果2018

    • Author(s)
      奥山由紀、平和伸仁、藤田恵美、藤原亮、江原洋介、谷津圭介、角田剛一郎、鍵本美奈子、勝又真理、小林雄祐、坂早苗、梅村敏、田村功一
    • Organizer
      第41回日本高血圧学会総会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Calcium metabolism in systemic heterozygous ATP2B1-null mice2017

    • Author(s)
      Yosuke Ehara, Nobuhito Hirawa, Kouichiro Sumida, Minako Kagimoto, Yuki Ooki, Megumi Fujita, Mari Katumata, Akira Fujiwara, Yusuke Kobayashi, Sanae Saka, Ikuma Katou, Keisuke Yatsu, Satoshi Umemura, and Kouichi Tamura
    • Organizer
      American Society of Nephrology Kidney Week 2017 Annual Meeting
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Decreased blood pressure in vascular smooth muscle specific ATP2B1 overexpressing mice2017

    • Author(s)
      Yosuke Ehara, Nobuhito Hirawa, Kouichiro Sumida, Minako Kagimoto, Yuki Ooki, Megumi Fujita, Mari Katumata, Akira Fujiwara, Yusuke Kobayashi, Sanae Saka, Ikuma Katou, Keisuke Yatsu, Satoshi Umemura, and Kouichi Tamura
    • Organizer
      American Society of Nephrology Kidney Week 2017 Annual Meeting
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] 血管平滑筋特異的ATP2B1ノックアウトマウスはCaチャネル拮抗薬に対する薬剤応答性を認めた2016

    • Author(s)
      奥山由紀,角田剛一郎,鍵本美奈子, 江原洋介,勝又真理,藤田恵美,藤原亮,小林雄祐,坂早苗,谷津圭介,梅村敏,平和伸仁
    • Organizer
      第39回日本高血圧学会総会
    • Place of Presentation
      仙台国際センター
    • Year and Date
      2016-09-30
    • Related Report
      2016 Research-status Report
  • [Presentation] ATP2B1血管平滑筋過剰発現マウスの作製と解析2016

    • Author(s)
      江原洋介,角田剛一郎,鍵本美奈子,奥山由紀,勝又真理,藤田恵美, 藤原亮,小林雄祐,坂早苗,谷津圭介,安田元,梅村敏,平和伸仁
    • Organizer
      第39回日本高血圧学会総会
    • Place of Presentation
      仙台国際センター
    • Year and Date
      2016-09-30
    • Related Report
      2016 Research-status Report

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Published: 2016-04-21   Modified: 2020-03-30  

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