Aldosterone production mechanisms mediated by ER calcium ion regulation.

• Project/Area Number: 17K09883
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Endocrinology
• Research Institution: Hiroshima University
• Principal Investigator: OKI KENJI 広島大学, 病院(医), 講師 (30638995)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: アルドステロン / 原発性アルドステロン症 / カルシウムシグナル / 二次性高血圧 / CALN1 / アンギオテンシンII / シグナル伝達

Outline of Final Research Achievements

Transcriptome analysis using aldosterone-producing adenomas revealed that CALN1 gene had the strongest correlation with CYP11B2 (aldosterone synthase) among genes encoding Ca2+ binding proteins. We modulated CALN1 in human adrenocortical carcinoma (HAC15) cells, and it showed increased Ca 2+ in the endoplasmic reticulum (ER). CYP11B2 expression and aldosterone production were potentiated in HAC15 cells by CALN1 expression. The silencing of CALN1 decreased Ca2+ in ER, and abrogated KCNJ5 mutation-mediated aldosterone production in HAC15 cells.

Academic Significance and Societal Importance of the Research Achievements

本研究により，細胞内カルシウムシグナルを介したアルドステロン合成機構の一端を解明することができた．CALN1は小胞体内の貯蔵カルシウムイオンを増加させ，さらには，細胞質内カルシウムシグナルを活性化させることによりアルドステロン合成を促進させる．CALN1を抑制することにより，原発性アルドステロン症(PA)におけるアルドステロン合成を抑制できる可能性があり，今後，CALN1を標的としたアルドステロン合成阻害薬に繋がる可能性がある．PAにおけるアルドステロン合成抑制薬の解明は，本邦での有病率が200～400万人と推定されるPAの診断や治療薬にも結びつく可能性がある．

Research Products

• [Int'l Joint Research] University of Mississippi Medical Center(米国)
• [Int'l Joint Research] University of Mississippi Medical Center(米国)
• [Int'l Joint Research] University of Mississippi Medical Center(米国)
• [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
• [Journal Article] A Rare Case of IgG4-Related Disease Presenting as a Unilateral Severe Dacryoadenitis Complicated by Hypophysitis and Hypertrophic Pachymeningitis. (2020)
  • Author(s): Yoshida Y, Kondo T, Hosokawa Y, Oki K, Yukawa K, Araki K, Kohno H, Kuranobu T, Tokunaga T, Oi K, Sugimoto T, Oda K, Nojima T, Hirata S, Sugiyama E.
  • Journal Title: J Clin Rheumatol Volume: - Issue: 8S Pages: S571-S573
  • DOI: 10.1097/rhu.0000000000000989
  • Peer Reviewed
• [Journal Article] Elevated Plasma Renin Activity Caused by Accelerated-malignant Hypertension in a Patient with Aldosterone-producing Adenoma Complicated with Renal Insufficiency (2019)
  • Author(s): Maruhashi T, Amioka M, Kishimoto S, Ikenaga H, Oki K, Ishida M, Kihara Y, Higashi Y.
  • Journal Title: Internal Medicine Volume: 58 Issue: 21 Pages: 3107-3111
  • DOI: 10.2169/internalmedicine.2327-18
  • NAID: 130007740769
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2019-11-01
  • Peer Reviewed
• [Journal Article] Alteration of gut microbiota by a Westernized lifestyle and its correlation with insulin resistance in non-diabetic Japanese men. (2019)
  • Author(s): Yamashita M, Okubo H, Kobuke K, Ohno H, Oki K, Yoneda M, Tanaka J, Hattori N.
  • Journal Title: J Diabetes Investig Volume: 10 Issue: 6 Pages: 1463-1470
  • DOI: 10.1111/jdi.13048
  • Peer Reviewed
• [Journal Article] Associations of nutrient intakes with obesity and diabetes mellitus in the longitudinal medical surveys of Japanese Americans. (2019)
  • Author(s): Sugihiro T, Yoneda M, Ohno H, Oki K, Hattori N.
  • Journal Title: J Diabetes Investig Volume: 10 Issue: 5 Pages: 1229-1236
  • DOI: 10.1111/jdi.13010
  • Peer Reviewed
• [Journal Article] Angiotensin 1-7 suppresses angiotensin II mediated aldosterone production via JAK/STAT signaling inhibition. (2019)
  • Author(s): Kobuke K, Oki K, Gomez-Sanchez CE, Ohno H, Itcho K, Yoshii Y, Yoneda M, Hattori N.
  • Journal Title: J Steroid Biochem Mol Biol Volume: 185 Pages: 137-141
  • DOI: 10.1016/j.jsbmb.2018.08.007
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Eplerenone improves endothelial function and arterial stiffness and inhibits Rho-associated kinase activity in patients with idiopathic hyperaldosteronism: a pilot study. (2019)
  • Author(s): Kishimoto S, Oki K, Maruhashi T, Kajikawa M, Matsui S, Hashimoto H, Takaeko Y, Kihara Y, Chayama K, Goto C, Aibara Y, Yusoff FM, Nakashima A, Noma K, Liao JK, Higashi Y.
  • Journal Title: J Hypertens Volume: 37 Issue: 5 Pages: 1083-1095
  • DOI: 10.1097/hjh.0000000000001989
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Microvascular endothelial function is impaired in patients with idiopathic hyperaldosteronism. (2018)
  • Author(s): Kishimoto S, Matsumoto T, Oki K, Maruhashi T, Kajikawa M, Matsui S, Hashimoto H, Kihara Y, Yusoff FM, Higashi Y.
  • Journal Title: Hypertens Res Volume: 41 Issue: 11 Pages: 932-938
  • DOI: 10.1038/s41440-018-0093-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Measurement of midnight ACTH levels is useful for the evaluation of midnight cortisol levels. (2018)
  • Author(s): Baba R, Oki K, Kobuke K, Itcho K, Okubo H, Ohno H, Yoneda M, Hattori N.
  • Journal Title: Steroids Volume: 140 Pages: 179-184
  • DOI: 10.1016/j.steroids.2018.10.011
  • Peer Reviewed / Open Access
• [Journal Article] Purkinje Cell Protein 4 Expression Is Associated With DNA Methylation Status in Aldosterone-Producing Adenoma. (2018)
  • Author(s): Kobuke K, Oki K, Gomez-Sanchez CE, Ohno H, Itcho K, Yoshii Y, Yoneda M, Hattori N.
  • Journal Title: J Clin Endocrinol Metab Volume: 103 Issue: 3 Pages: 965-971
  • DOI: 10.1210/jc.2017-01996
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Calneuron 1 Increased Ca2+ in the Endoplasmic Reticulum and Aldosterone Production in Aldosterone-Producing Adenoma (2018)
  • Author(s): Kobuke K, Oki K, Gomez-Sanchez CE, Gomez-Sanchez EP, Ohno H, Itcho K, Yoshii Yoko, Yoneda M, Hattori, N.
  • Journal Title: Hypertension Volume: 71 Issue: 1 Pages: 125-133
  • DOI: 10.1161/hypertensionaha.117.10205
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Aberrant G protein-receptor expression is associated with DNA methylation in aldosterone-producing adenoma (2018)
  • Author(s): Itcho K, Oki K, Kobuke K, Yoshii Y, Ohno H, Yoneda M, Hattori N.
  • Journal Title: Mol Cell Endocrinol Volume: 461 Pages: 100-104
  • DOI: 10.1016/j.mce.2017.08.019
  • Peer Reviewed
• [Journal Article] NFIA co-localizes with PPARγ and transcriptionally controls the brown fat gene program. (2017)
  • Author(s): Hiraike Y, Waki H, Yu J, Nakamura M, Miyake K, Nagano G, Nakaki R, Suzuki K, Kobayashi H, Yamamoto S, Sun W, Aoyama T, Hirota Y, Ohno H, Oki K, Yoneda M, White AP, Tseng YH, Cypess AM, Larsen TJ, Jespersen NZ, Scheele C, Tsutsumi S, Aburatani H, Yamauchi T, Kadowaki T
  • Journal Title: Nature cell biology Volume: 19(9) Issue: 9 Pages: 1081-1092
  • DOI: 10.1038/ncb3590
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Westernization of lifestyle affects quantitative and qualitative changes in adiponectin (2017)
  • Author(s): Kubota M, Yoneda M, Maeda N, Ohno H, Oki K, Funahashi T, Shimomura I, Hattori N.
  • Journal Title: Cardiovasc Diabetol Volume: 16 Issue: 1 Pages: 83-83
  • DOI: 10.1186/s12933-017-0565-z
  • Peer Reviewed / Open Access
• [Journal Article] Association between Serum Elaidic Acid Concentration and Insulin Resistance in Two Japanese Cohorts with Different Lifestyles (2017)
  • Author(s): Itcho K, Yoshii Y, Ohno H, Oki K, Shinohara M, Irino Y, Toh R, Ishida T, Hirata KI, Yoneda M.
  • Journal Title: Journal of Atherosclerosis and Thrombosis Volume: 24 Issue: 12 Pages: 1206-1214
  • DOI: 10.5551/jat.39164
  • NAID: 130006235272
  • ISSN: 1340-3478, 1880-3873
  • Peer Reviewed / Open Access
• [Journal Article] Effect of miglitol on the suppression of nonalcoholic steatohepatitis development and improvement of the gut environment in a rodent model (2017)
  • Author(s): Kishida Yumi, Okubo Hirofumi, Ohno Haruya, Oki Kenji, Yoneda Masayasu
  • Journal Title: Journal of Gastroenterology Volume: Epub ahead of print Issue: 11 Pages: 1180-1191
  • DOI: 10.1007/s00535-017-1331-4
  • Peer Reviewed / Open Access
• [Journal Article] Increased Calcium Ion Levels Following Systemic Circulation After the Selective Arterial Calcium Injection Test (2017)
  • Author(s): Egusa G, Oki K, Yoshii Y, Kubota M, Okubo H, Ohno H, Kajiwara K, Awai K, Yoneda M.
  • Journal Title: Pancreas Volume: 46 Issue: 4 Pages: e34-e35
  • DOI: 10.1097/mpa.0000000000000803
• [Presentation] 夜間ACTH高値が副腎性サブクリニカルクッシング症候群診断に与える影響 (2019)
  • Author(s): 馬場 隆太, 沖 健司, 児玉 尭也, 一町 澄宜, 小武家 和博, 長野 学, 大久保 博史, 大野 晴也, 米田 真康
  • Organizer: 第92回日本内分泌学会学術総会
• [Presentation] ATP1A1変異によるアルドステロン産生腺腫増殖機構の解明 (2019)
  • Author(s): 小武家 和博, 沖 健司, 馬場 隆太, 一町 澄宜, 長野 学, 大久保 博史, 大野 晴也, 米田 真康
  • Organizer: 第92回日本内分泌学会学術総会
• [Presentation] 分子シャペロンCLGNはアルドステロン産生腫瘍に特異的に発現しアルドステロン合成に関与する (2019)
  • Author(s): 一町 澄宜, 沖 健司, 馬場 隆太, 小武家 和博, 大久保 博史, 大野 晴也, 米田 真康
  • Organizer: 第92回日本内分泌学会学術総会
• [Presentation] 副腎静脈サンプリングにおける最適な局在判定基準は (2019)
  • Author(s): 沖 健司
  • Organizer: 第92回日本内分泌学会学術総会
• [Presentation] ER chaperone calmegin is upregulated in aldosterone-producing adenoma and associates with aldosterone production (2019)
  • Author(s): Kenji Oki, Kiyotaka Itcho, Celso E. Gomez-Sanchez, Elise P. Gomez-Sanchez, Kazuhiro Kobuke, Ryuta Baba, Haruya Ohno, Masayasu Yoneda, Noboru Hattori
  • Organizer: Progress in Primary Aldosteronisum 6
  • Int'l Joint Research
• [Presentation] ATP1A1 mutation stimulates adrenal cell proliferation via vitamin D receptor signal induced by DNA demethylation (2019)
  • Author(s): Yuta Nanao, Kenji Oki, Celso E. Gomez-Sanchez, Kazuhiro Kobuke, Kiyotaka Itcho, Ryuta Baba, Haruya Ohno, Masayasu Yoneda, Noboru Hattori
  • Organizer: 44th Meeting of the International Aldosterone Conference
  • Int'l Joint Research
• [Presentation] Ouabain induced aldosterone production and cell proliferation in ATP1A1 mutated aldosterone-producing adenoma (2019)
  • Author(s): Kazuhiro Kobuke, Kenji Oki, Kiyotaka Itcho, Ryuta Baba, Haruya Ohno, Masayasu Yoneda, Noboru Hattori
  • Organizer: 44th Meeting of the International Aldosterone Conference
  • Int'l Joint Research
• [Presentation] Molecular chaperone CLGN associates with aldosterone production in APA and APCC. (2019)
  • Author(s): Kiyotaka Itcho, Kenji Oki, Celso E. Gomez-Sanchez, Elise P. Gomez-Sanchez, Kazuhiro Kobuke, Ryuta Baba, Haruya Ohno, Masayasu Yoneda, Noboru Hattori
  • Organizer: 44th Meeting of the International Aldosterone Conference
  • Int'l Joint Research
• [Presentation] 分子生物学的解析から原発性アルドステロン症の成因に迫る (2018)
  • Author(s): 沖 健司
  • Organizer: 第28回臨床内分泌代謝Update
  • Invited
• [Presentation] 分子シャペロンCLGNはアルドステロン産生腫瘍において発現上昇しアルドステロン合成を調節する (2018)
  • Author(s): 一町澄宜，沖健司，小武家和博，大野晴也，米田真康
  • Organizer: 第91回日本内分泌学会学術総会
• [Presentation] Molecular chaperone Calmegin is up-regulated in aldosterone-producing adenoma and associates with aldosterone production (2018)
  • Author(s): Kiyotaka Itcho, Kenji Oki, Celso E. Gomez-Sanchez, Elise P. Gomez-Sanchez, Kazuhiro Kobuke, Ryuta Baba, Haruya Ohno, Masayasu Yoneda, Noboru Hattori
  • Organizer: 43th Meeting of the International Aldosterone Meeting
  • Int'l Joint Research
• [Presentation] Angiotensin 1-7 repress Angiotensin II mediated aldosterone production via JAK/STAT signaling inhibition (2018)
  • Author(s): Ryuta Baba, Kenji Oki, Kiyotaka Itcho, Kazuhiro Kobuke, Haruya Ohno, Masayasu Yoneda, Noboru Hattori
  • Organizer: 43th Meeting of the International Aldosterone Meeting
  • Int'l Joint Research
• [Presentation] 対側にコルチゾール産生腫瘍を合併したアルドステロン産生腫瘍の1例 (2017)
  • Author(s): 木村文香、馬場隆太、沖健司、山本祐太郎、江草玄太郎、小武家和博、大久保博史、大野晴也、米田真康
  • Organizer: 第117回日本内科学会中国地方会
• [Presentation] APAとSubCSを合併した両側副腎腫瘍の1例 (2017)
  • Author(s): 岡田康平、一町澄宜、沖健司、馬場隆太、江草玄太郎、小武家和博、大久保博史、大野晴也、米田真康
  • Organizer: 第27回臨床内分泌代謝Update
• [Presentation] Aldosterone Production via Endoplasmic Reticulum Function in Aldosterone-producing Adenoma (2017)
  • Author(s): Kenji Oki, Kazuhiro Kobuke, Celso E. Gomez-Sanchez, Elise P. Gomez-Sanchez, Kiyotaka Itcho, Yoko Yoshii, Haruya Ohno, Masayasu Yoneda, Noboru Hattori.
  • Organizer: Hypertension Forum of Western Great Wall of China
  • Int'l Joint Research / Invited
• [Presentation] 原発性アルドステロン症の局在診断における副腎静脈サンプリングの後ろ向き検討． (2017)
  • Author(s): 沖健司，久保田益亘，吉井陽子，江草玄太郎，岸本真治，池永寛樹，大久保博史，大野晴也，米田真康．
  • Organizer: 第114回日本内科学会学術総会
• [Presentation] Ca2+結合タンパクcalneuron1を介したアルドステロン合成調節機構 (2017)
  • Author(s): 小武家和博、一町澄宜、吉井陽子、沖健司、大野晴也、米田真康
  • Organizer: 第90回日本内分泌学会学術総会
• [Presentation] 新基準に基づく原発性アルドステロン症の局在診断への影響 (2017)
  • Author(s): 小根森陽子、沖健司、江草玄太郎、岸田祐美、吉井陽子、森田好美、小武家和博、長野学、一町澄宜、久保田益亘、大久保博史、大野晴也、米田真康
  • Organizer: 第90回日本内分泌学会学術総会
• [Presentation] アルドステロン産生腺腫におけるステロイド合成酵素のエピジェネティック調節機構 (2017)
  • Author(s): 吉井陽子、沖健司、小武家和博、一町澄宜、大野晴也、米田真康
  • Organizer: 第90回日本内分泌学会学術総会