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The identification of undetermined adipocyte-derived factor(s) that stimulate aldosterone synthase gene (CYP11B2) expression

Research Project

Project/Area Number 16H03252
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Applied health science
Research InstitutionTohoku University

Principal Investigator

Sugawara Akira  東北大学, 医学系研究科, 教授 (90270834)

Research Collaborator YOKOYAMA atushi  
KUDO masataka  
DOI takayuki  
ITO ryo  
SHIMADA hiroki  
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥8,190,000 (Direct Cost: ¥6,300,000、Indirect Cost: ¥1,890,000)
Fiscal Year 2018: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
Fiscal Year 2017: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
Fiscal Year 2016: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
Keywordsアルドステロン / 肥満 / 高血圧 / 脂肪細胞 / CYP11B2 / 肥満高血圧 / 創薬 / 新規創薬
Outline of Final Research Achievements

Obese patients are well known to be highly complicated with hypertension. Recently, “undetermined” adipocyte-derived factor(s) have been recognized as one of the causes of the obesity-related hypertension independent of angiotensin II. In the present study, we aim to identify the undetermined adipocyte-derived factor(s) that stimulate aldosterone synthase gene (CYP11B2) expression and aldosterone secretion that may induce hypertension. We first differentiated mouse fibroblast 3T3-L1 cells into adipocytes, and collected their supernatants. The supernatants were then incubated with human adrenocortical carcinoma H295R cells, and their ability to stimulate CYP11B2 mRNA expression was indicated. Thereafter, the supernatants were fractionated by ultrafiltration to obtain active fractions that stimulate CYP11B2 expression, and proteins included in the fractions were analyzed by LC-MS/MS. We finally obtained factor "X" which was demonstrated to stimulate CYP11B2 expression significantly.

Academic Significance and Societal Importance of the Research Achievements

肥満患者における高血圧の制御は、国民の健康寿命延伸・医療費削減の両面から喫緊の課題である。本研究課題の遂行により新規昇圧因子"X"が得られたが、今後は本因子を基盤とした肥満高血圧の新規診断・治療法の開発を進める。これらの遂行により、肥満高血圧に起因する心血管イベントの発症を二次的に抑制することが可能となり、患者さんへの福音となるとともに、本邦の医療費抑制にも大きく貢献することが期待される。

Report

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

    (22 results)

All 2018 2017 2016 Other

All Journal Article (8 results) (of which Int'l Joint Research: 7 results,  Peer Reviewed: 8 results,  Open Access: 8 results) Presentation (12 results) (of which Int'l Joint Research: 11 results) Remarks (1 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] Endogenous Purification of NR4A2 (Nurr1) Identified Poly(ADP-Ribose) Polymerase 1 as a Prime Coregulator in Human Adrenocortical H295R Cells.2018

    • Author(s)
      Noro, E., Yokoyama, A., Kobayashi, M., Shimada, H., Suzuki, S., Hosokawa, M., Takehara, T., Parvin, R., Shima, H., Igarashi, K. and Sugawara A.
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 19 Issue: 5 Pages: 1406-1406

    • DOI

      10.3390/ijms19051406

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The reduction of heparan sulphate in the glomerular basement membrane does not augment urinary albumin excretion2018

    • Author(s)
      Satoshi Aoki, Akiko Saito-Hakoda, Takeo Yoshikawa, Kyoko Shimizu, Kiyomi Kisu, Susumu Suzuki, Kiyoshi Takagi, Shuji Mizumoto, Shuhei Yamada, Toin H. van Kuppevelt, Atsushi Yokoyama, Taiji Matsusaka, Hiroshi Sato, Sadayoshi Ito, and Akira Sugawara
    • Journal Title

      Nephrology Dialysis Transplantation

      Volume: 33 Issue: 1 Pages: 26-33

    • DOI

      10.1093/ndt/gfx218

    • Related Report
      2018 Annual Research Report 2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Inhibitory Effects of a Novel PPAR-γ Agonist MEKT1 on Pomc Expression/ACTH Secretion in AtT20 Cells.2018

    • Author(s)
      Parvin R, Noro E, Saito-Hakoda A, Shimada H, Suzuki S, Shimizu K, Miyachi H, Yokoyama A, Sugawara A
    • Journal Title

      PPAR Res

      Volume: 2018 Pages: 5346272-5346272

    • DOI

      10.1155/2018/5346272

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Heparan sulfate in pancreatic β-cells contributes to normal glucose homeostasis by regulating insulin secretion.2018

    • Author(s)
      Matsuzawa T, Yoshikawa T, Iida T, Karpati A, Kitano H, Harada R, Nakamura T, Sugawara A, Yamaguchi Y, Yanai K.
    • Journal Title

      Biochem Biophys Res Commun

      Volume: - Issue: 3 Pages: 688-695

    • DOI

      10.1016/j.bbrc.2018.03.213

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Crucial role of Reg I from acinar-like cell cluster touching with islets (ATLANTIS) on mitogenesis of beta cells in EMC virus-induced diabetic mice2018

    • Author(s)
      Aida Kaoru、Kobayashi Tetsuro、Takeshita Akira、Jimbo Erika、Nishida Yoriko、Yagihashi Soroku、Hosoi Mitsuko、Fukui Tomoyasu、Sugawara Akira、Takasawa Shin
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 503 Issue: 2 Pages: 963-969

    • DOI

      10.1016/j.bbrc.2018.06.103

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Suppressive effects of RXR agonist PA024 on adrenal CYP11B2 expression, aldosterone secretion and blood pressure2017

    • Author(s)
      Suzuki Dai、Saito-Hakoda Akiko、Ito Ryo、Shimizu Kyoko、Parvin Rehana、Shimada Hiroki、Noro Erika、Suzuki Susumu、Fujiwara Ikuma、Kagechika Hiroyuki、Rainey William E.、Kure Shigeo、Ito Sadayoshi、Yokoyama Atsushi、Sugawara Akira
    • Journal Title

      PLoS One

      Volume: 12 Issue: 8 Pages: e0181055-e0181055

    • DOI

      10.1371/journal.pone.0181055

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] High glucose stimulates expression of aldosterone synthase (CYP11B2) and secretion of aldosterone in human adrenal cells2017

    • Author(s)
      Shimada Hiroki、Kogure Naotaka、Noro Erika、Kudo Masataka、Sugawara Kaori、Sato Ikuko、Shimizu Kyoko、Kobayashi Makoto、Suzuki Dai、Parvin Rehana、Saito-Ito Takako、Uruno Akira、Saito-Hakoda Akiko、Rainey William E.、Ito Sadayoshi、Yokoyama Atsushi、Sugawara Akira
    • Journal Title

      FEBS Open Bio

      Volume: 7 Issue: 9 Pages: 1410-1421

    • DOI

      10.1002/2211-5463.12277

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Role of NeuroD1 on the negative regulation of Pomc expression by glucocorticoid.2017

    • Author(s)
      Parvin R, Saito-Hakoda A, Shimada H, Shimizu K, Noro E, Iwasaki Y, Fujiwara K, Yokoyama A, Sugawara A.
    • Journal Title

      PLoS One.

      Volume: 12(4) Issue: 4 Pages: e0175435-e0175435

    • DOI

      10.1371/journal.pone.0175435

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Possible Involvement of ChREBP in the Progression of Diabetic Kidney Disease in the Renal Tubules.2018

    • Author(s)
      Suzuki S, Noro E, Aoki S, Parvin R, Shimada H, Yokoyama A, Sugawara A
    • Organizer
      ISN Frontiers Meetings
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Angiotensin II causes synergistic effects for the ligand activation of farnesoid X receptor (FXR).2018

    • Author(s)
      Shimada H, Noro E, Sato I, Suzuki S, Parvin R, Sakamoto J, Yokoyama A, Sugawara A
    • Organizer
      ENDO2018
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Involvement of IKK complex in the regulation of a glucose-responsive transcriptional factor ChREBP in pancreatic β-cell.2018

    • Author(s)
      Noro E, Yokoyama A, Kogure N, Momma R, Shimizu K, Parvin R, Suzuki S, Shimada H, Shima H, Igarashi K, Sugawara A
    • Organizer
      ENDO2018
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] MEKT1, a novel PPAR-gamma agonist, significantly suppressed Pomc expression/ACTH secretion in AtT20 cells.2018

    • Author(s)
      Parvin R, Saito-Hakoda A, Shimada H, Noro E, Suzuki S, Miyachi H, Yokoyama A, Sugawara A
    • Organizer
      ENDO2018
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Identification of novel AR coregulators via endogenous purification.2018

    • Author(s)
      Yokoyama A, Noro E, Kobayashi M, Shimizu K, Shimada H, Suzuki S, Shima H, Igarashi K, Sugawara A
    • Organizer
      ENDO2018
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] MEKT1, a novel PPAR-gamma agonist, significantly suppressed Pomc expression/ACTH secretion in AtT20 cells2018

    • Author(s)
      Rehana Parvin, Akiko Saito-Hakoda, Hiroki Shimada, Erika Noro, Susumu Suzuki, Hiroyuki Miyachi Atsushi Yokoyama, Akira Sugawara
    • Organizer
      ENDO2018
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Involvement of IKK complex in the regulation of a glucose-responsive transcriptional factor ChREBP in pancreatic β-cell2018

    • Author(s)
      Erika Noro, Atsushi Yokoyama, Naotaka Kogure, Rina Momma, Kyoko Shimizu, Rehana Parvin, Susumu Suzuki, Hiroki Shimada, Hiroki Shima, Kazuhiko Igarashi, Akira Sugawara
    • Organizer
      ENDO2018
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Generation and functional analyses of stable H295R cell lines expressing mutants KCNJ5 proteins2018

    • Author(s)
      Ryo Ito, Ikuko Sato, Keita Hoshi, Akira Sugawara
    • Organizer
      ENDO2018
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Possible Involvement of ChREBP in the Progression of Diabetic Kidney Disease in the Renal Tubules2018

    • Author(s)
      Susumu Suzuki, Atsushi Yokoyama, Erika Noro, Satoshi Aoki, Rehana Parvin, Hiroki Shimada, Akira Sugawara
    • Organizer
      ISN Frontiers Meeting 2018
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] A novel approach for the identification of undetermined adipocyte-derived factor(s) that stimulate aldosterone synthase gene (CYP11B2) expression2016

    • Author(s)
      Hiroki Shimada, Ryo Ito, Ikuko Sato, Emiko Sato, Atsushi Yokoyama, Akira Sugawara
    • Organizer
      ENDO2016
    • Place of Presentation
      アメリカ合衆国ボストン市
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 脂肪細胞培養上清中に含まれる副腎アルドステロン合成酵素発現誘導因子の探索2016

    • Author(s)
      島田洋樹、伊藤 亮、佐藤恵美子、横山 敦、菅原 明
    • Organizer
      第89回日本内分泌学会学術総会
    • Place of Presentation
      京都(国立京都国際会館)
    • Related Report
      2016 Annual Research Report
  • [Presentation] An approach to identify the undetermined adipocyte-derived factor(s) that stimulate aldosterone synthase gene (CYP11B2) expression2016

    • Author(s)
      Hiroki Shimada, Ryo Ito, Emiko Sato, Atsushi Yokoyama, Akira Sugawara
    • Organizer
      The 9th International Aldosterone Forum in Japan
    • Place of Presentation
      東京(ザ・グランドホール)
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Remarks] 東北大学大学院医学系研究科・分子内分泌学分野

    • URL

      http://www.med.tohoku.ac.jp/about/laboratory/189.html

    • Related Report
      2016 Annual Research Report
  • [Patent(Industrial Property Rights)] アルドステロン合成酵素発現阻害剤2017

    • Inventor(s)
      菅原明
    • Industrial Property Rights Holder
      菅原明
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2017-064702
    • Filing Date
      2017
    • Acquisition Date
      2018
    • Related Report
      2018 Annual Research Report

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

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