Mechanism of RXR-mediated cell proliferation in aldosterone-producing adenomas based on epigenomic regulation

• Project/Area Number: 19K17972
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54040:Metabolism and endocrinology-related
• Research Institution: Department of Clinical Research, National Hospital Organization Kure Medical Center
• Principal Investigator: Yoshii Yoko 独立行政法人国立病院機構(呉医療センター臨床研究部), その他部局等, その他 (00795320)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 原発性アルドステロン症 / 内分泌 / 高血圧 / primary aldosteronism / hypertension / aldosterone / vitamin D receptor / 腫瘍増殖 / アルドステロン / RXR / エピゲノム / アルドステロン合成 / DNAメチル化

Outline of Research at the Start

申請者はアルドステロン産生腺腫（APA）におけるDNAメチル化を基盤にしたアルドステロン合成制御機構の解明から創薬基盤因子の探索行ってきた．これまでの研究結果から，レチノイドX受容体（RXR）共役因子Xは，プロモーター領域の脱メチル化により転写が促進され，APAに発現するATPase体細胞変異がその脱メチル化を誘導することをている．本研究ではRXRを介したAPAの腫瘍増殖機構およびアルドステロン合成制御における合成機構を解明することを目的とする．

Outline of Final Research Achievements

Primary aldosteronism (PA) is a common disease that accounts for 5-10% of hypertensive patients. PA is classified into aldosterone-producing adenoma (APA) and idiopathic hyperaldosteronism, both of which overproduce aldosterone and are associated with cardiovascular disease. In this study, we show that VDR expression induced by DNA hypomethylation is essential for cell proliferation in ATP1A1 mutant APA and that NKA stimulation is involved in the proliferation of ATP1A1 mutant APA. These findings lead to the identification of therapeutic target factors for APA.

Academic Significance and Societal Importance of the Research Achievements

原発性アルドステロン症 (PA) は高血圧患者の5-10%程度を占める頻度の高い疾患で，アルドステロンを過剰産生することで高血圧を発症するだけではなく心血管疾患を合併しやすい.そのため，PAの早期診断や治療，アルドステロン合成の制御は重要である.本研究ではアルドステロン産生腺腫におけるアルドステロン過剰産生や細胞増殖機構の一部を解明し，PAにおける治療標的や予防法の開発に役立つ可能性がある.

Research Products

• [Int'l Joint Research] University of Mississippi Medical Center(米国)
• [Journal Article] ATP1A1 Mutant in Aldosterone-Producing Adenoma Leads to Cell Proliferation (2021)
  • Author(s): Kobuke Kazuhiro、Oki Kenji、Gomez-Sanchez Celso E.、Gomez-Sanchez Elise P.、Itcho Kiyotaka、Ohno Haruya、Nagano Gaku、Yoshii Yoko、Baba Ryuta、Kodama Takaya、Arihiro Koji、Hattori Noboru、Yoneda Masayasu
  • Journal Title: International Journal of Molecular Sciences Volume: 22 Issue: 20 Pages: 10981-10981
  • DOI: 10.3390/ijms222010981
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Endoplasmic Reticulum Chaperone Calmegin Is Upregulated in Aldosterone-Producing Adenoma and Associates With Aldosterone Production. (2020)
  • Author(s): Itcho K, Oki K, Gomez-Sanchez CE, Gomez-Sanchez EP, Ohno H, Kobuke K, Nagano G, Yoshii Y, Baba R, Hattori N, Yoneda M.
  • Journal Title: Hypertension Volume: 75 Issue: 2 Pages: 492-499
  • DOI: 10.1161/hypertensionaha.119.14062
  • Peer Reviewed / Int'l Joint Research