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

• Project/Area Number: 16H03252
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Applied health science
• Research Institution: Tohoku University
• Principal Investigator: 菅原 明 東北大学, 医学系研究科, 教授 (90270834)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥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 Annual Research Achievements

メタボリック症候群・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。近年、脂肪細胞由来の未知の液性昇圧因子が直接副腎に作用することによりアンジオテンシンIIとは独立してCYP11B2発現・アルドステロン分泌を亢進させ、肥満高血圧症の原因となっている可能性が示唆されている。本研究の目的は、同因子を単離・同定して機能解析を行った後、同因子を標的とした肥満高血圧症の新規創薬を進めることである。まず、ヒト副腎腫瘍由来H295R細胞に脂肪細胞より取得した培養上清を添加し、CYP11B2の発現誘導を指標に分子量による分画を行った。その結果、CYP11B2発現誘導能を有する画分を見出した。次に、同画分を質量分析装置にて解析することにより、液性因子の同定を行った。その結果、52種類の候補因子が同定された。さらに、それらの中からシグナルペプチドの存在が想定された12種類の因子を同定した。これらの因子中にはタンパク分解酵素AならびにAの作用により活性化する因子Bが含まれていた。そこで、タンパク分解酵素阻害剤の投与実験ならびに活性化されたBの受容体に対する阻害剤の投与実験を行ったところ、いずれにおいても培養上清が有するCYP11B2発現誘導活性の低下が認められた。以上の結果から、タンパク分解酵素AとAの作用により活性化する因子Bは脂肪細胞培養上清におけるCYP11B2発現誘導因子の有望な候補因子であることが示唆された。今後の本プロジェクトの遂行により、肥満高血圧症の新規創薬・治療法の開発が進むものと期待される。

Research Progress Status

平成30年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

平成30年度が最終年度であるため、記入しない。

Research Products

• [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: Int J Mol Sci Volume: 19 Pages: 1406-1406
  • DOI: 10.3390/ijms19051406
  • 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 excretion. (2018)
  • 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: Nephrol. Dial. Transplant. Volume: 33 Pages: 26-33
  • DOI: 10.1093/ndt/gfx218
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Inhibitory effects of a novel PPAR-gamma 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: 1-16
  • DOI: 10.1155/2018/5346272
  • 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: Biochemical and Biophysical Research Communications Volume: - Pages: 688-695
  • DOI: 10.1016/j.bbrc.2018.03.213
  • 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 mice (2018)
  • Author(s): Aida Kaoru、Kobayashi Tetsuro、Takeshita Akira、Jimbo Erika、Nishida Yoriko、Yagihashi Soroku、Hosoi Mitsuko、Fukui Tomoyasu、Sugawara Akira、Takasawa Shin
  • Journal Title: Biochem Biophys Res Commun Volume: 503 Pages: 963-969
  • DOI: 10.1016/j.bbrc.2018.06.103
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Suppressive effects of RXR agonist PA024 on adrenal CYP11B2 expression, aldosterone secretion and blood pressure. (2017)
  • 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
  • DOI: 10.1371/journal.pone.0181055
  • 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 cells. (2017)
  • 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 Pages: 1410-1421
  • DOI: 10.1002/2211-5463.12277
  • 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)
  • DOI: 10.1371/journal.pone.0175435
  • 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
  • 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
  • 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
  • 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
  • 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
  • Int'l Joint Research
• [Presentation] MEKT1, a novel PPAR-gamma agonist, significantly suppressed Pomc expression/ACTH secretion in AtT20 cells (2018)
  • Author(s): Rehana Parvin, Akiko Saito-Hakoda, Hiroki Shimada, Erika Noro, Susumu Suzuki, Hiroyuki Miyachi Atsushi Yokoyama, Akira Sugawara
  • Organizer: ENDO2018
  • 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): Erika Noro, Atsushi Yokoyama, Naotaka Kogure, Rina Momma, Kyoko Shimizu, Rehana Parvin, Susumu Suzuki, Hiroki Shimada, Hiroki Shima, Kazuhiko Igarashi, Akira Sugawara
  • Organizer: ENDO2018
  • Int'l Joint Research
• [Presentation] Generation and functional analyses of stable H295R cell lines expressing mutants KCNJ5 proteins (2018)
  • Author(s): Ryo Ito, Ikuko Sato, Keita Hoshi, Akira Sugawara
  • Organizer: ENDO2018
  • Int'l Joint Research
• [Presentation] Possible Involvement of ChREBP in the Progression of Diabetic Kidney Disease in the Renal Tubules (2018)
  • Author(s): Susumu Suzuki, Atsushi Yokoyama, Erika Noro, Satoshi Aoki, Rehana Parvin, Hiroki Shimada, Akira Sugawara
  • Organizer: ISN Frontiers Meeting 2018
  • Int'l Joint Research
• [Presentation] A novel approach for the identification of undetermined adipocyte-derived factor(s) that stimulate aldosterone synthase gene (CYP11B2) expression (2016)
  • 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
  • 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）
• [Presentation] An approach to identify the undetermined adipocyte-derived factor(s) that stimulate aldosterone synthase gene (CYP11B2) expression (2016)
  • 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）
  • 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
• [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
  • Application Year: 2017
  • Acquisition Date: 2018
  • Acquisition Year: 2018