Adrenocortical remodeling develops autonomous production of aldosterone

• Project/Area Number: 26461387
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Endocrinology
• Research Institution: Keio University
• Principal Investigator: MUKAI KUNIAKI 慶應義塾大学, 医学部(信濃町), 専任講師 (80229913)
• Co-Investigator(Kenkyū-buntansha): 樋口 明弘 大分大学, 学内共同利用施設等, 講師 (20383755) ; 荻島 正 九州大学, 理学研究院, 准教授 (70177153)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: アルドステロン / ステロイドホルモン / 副腎

Outline of Final Research Achievements

Aldosterone is secreted from adrenal cortex in mammals and has an essential role for homeostasis of body fluid volume. Formation of excessive aldosterone-producing lesions such as adrenal adenomas causes primary aldosteronism in humans. This study focused on pathogenesis of primary aldosteronism and examined excessive aldosterone-producing lesions from patients by using histochemical methods and gene mutation analyses. The results suggested that an aldosterone-producing cell-cluster, which we previously discovered in normal human adrenal cortex, could develop to a transitional lesion further growing to an adenoma. Somatic mutations of a group of ion channel/pump genes were likely to play key roles for development from an aldosterone-producing cell-cluster to an adenoma through such a transitional lesion.

Research Products

• [Journal Article] Disorganized steroidogenesis in adrenocortical carcinoma, a case study (2017)
  • Author(s): Uchida, T., Nishimoto, K., Fukumura, Y., Asahina, M., Goto, H., Kawano, Y., Shimizu, F., Tsujimura, A., Seki, T., Mukai, K., Kabe, Y., Suematsu, M., Gomez-Sanchez, C.E., Yao, T., Horie, S., Watada, H.
  • Journal Title: Endocr. Pathol. Volume: 28 Issue: 1 Pages: 27-35
  • DOI: 10.1007/s12022-016-9441-8
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Immunohistochemistry of aldosterone synthase leads the way to the pathogenesis of primary aldosteronism (2017)
  • Author(s): Nishimoto, K., Koga, M., Seki, T., Oki, K., Gomez-Sanchez, E.P., Gomez-Sanchez, C.E., Naruse, M., Sakaguchi, T., Morita, S., Kosaka, T., Oya, M., Ogishima, T., Yasuda, M., Suematsu, M., Kabe, T., Omura, M., Nishikawa, T., Mukai, K.
  • Journal Title: Mol. Cell. Endocrinol. Volume: 441 Pages: 124-133
  • DOI: 10.1016/j.mce.2016.10.014
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Somatic KCNJ5 mutation occurring early in adrenal development may cause a novel form of juvenile primary aldosteronism. (2017)
  • Author(s): Tamura A, Nishimoto K, Seki T, Matsuzawa Y, Saito J, Omura M, Gomez-Sanchez CE, Makita K, Matsui S, Moriya N, Inoue A, Nagata M, Sasano H, Nakamura Y, Yamazaki Y, Kabe Y, Mukai K, Kosaka T, Oya M, Suematsu S, Nishikawa T.
  • Journal Title: Mol Cell Endocrinol. Volume: 441 Pages: 134-139
  • DOI: 10.1016/j.mce.2016.07.031
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Human adrenocortical remodeling leading to aldosterone-producing cell cluster generation (2016)
  • Author(s): Nishimoto, K., Seki, T., Hayashi, Y., Mikami, S., Al-Eyd, G., Nakagawa, K., Morita, S., Kosaka, T., Oya, M., Mitani, F., Suematsu, M., Kabe, T., Mukai, K.
  • Journal Title: Int. J. Endocrinol. Volume: 2016 Pages: 7834356-7834356
  • DOI: 10.1155/2016/7834356
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Temporal and spatial distribution of mast cells and steroidogenic enzymes in the human fetal adrenal (2016)
  • Author(s): Naccache, A., Louiset, E., Duparc, C., Laquerriere, A., Patrier, S., Renouf, S., Gomez-Sanchez C.E., Mukai, K., Lefebvre, H., Castanet, M.
  • Journal Title: Mol. Cell. Endocrinol. Volume: 434 Pages: 69-80
  • DOI: 10.1016/j.mce.2016.06.015
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] 11-ketotestosterone is a major androgen produced in human gonads (2016)
  • Author(s): Imamichi, Y., Yuhki, K.-I., Orisaka, M., Kitano, T., Mukai, K., Ushikubi, F., Taniguchi, T., Umezawa, A., Miyamoto, K., Yazawa, T.
  • Journal Title: J. Clin. Endocrinol. Metab. Volume: 101 Issue: 10 Pages: 3582-3591
  • DOI: 10.1210/jc.2016-2311
  • NAID: 120006348221
  • Peer Reviewed
• [Journal Article] Impaired female fertility in Tubulointerstitial antigen-like 1 deficient mice (2016)
  • Author(s): Takahashi, A., Rahim, A., Takeuchi, M., Fukui, E., Yoshizawa, M., Mukai, K., Suematsu, M., Hasuwa, H., Okabe, M., Matsumoto, H.
  • Journal Title: J. Reprod. Dev. Volume: 62 Pages: 43-49
  • NAID: 130005126314
  • Peer Reviewed / Open Access
• [Journal Article] A case report: Nodule development from subcapsular aldosterone-producing cell clusters causes hyperaldosteronism (2016)
  • Author(s): Nishimoto K, Seki T, Kurihara I, Yokota K, Omura M, Nishikawa T, Shibata H, Kosaka T, Oya M, Suematsu M, Mukai K
  • Journal Title: J Clin Endocrinol Metab Volume: 101 Issue: 1 Pages: 6-9
  • DOI: 10.1210/jc.2015-3285
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] A novel CYP11B2-specific positron emission tomography imaging agent for detection of aldosterone-producing adenomas (2016)
  • Author(s): Abe, T., Naruse, M., Young Jr. W. F., Kobashi, N., Doi, Y., Izawa, A., Akama, K., Okumura, Y., Ikenaga, M., Kimura, H., Saji, H., Mukai, K., Matsumoto, H.
  • Journal Title: J. Clin. Endocrinol. Metab. Volume: 101 Issue: 3 Pages: 1008-1015
  • DOI: 10.1210/jc.2015-3431
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] CYP11B2免疫染色がひらく原発性アルドステロン症発症機構の解明 (2016)
  • Author(s): 西本紘嗣郎, 向井 邦晃
  • Journal Title: 最新医学 Volume: 71
• [Journal Article] Mast cell hyperplasia is associated with aldosterone hypersecretion in a subset of aldosterone-producing adenomas (2015)
  • Author(s): Duparc, C., Moreau L., Dzib, J.F., Boyer, H.G., Tetsi Nomigni, M., Boutelet, I., Boulkroun, S., Mukai, K., Benecke, A.G., Amar, L., Gobet, F., Meatchi, T., Plouin, P.F., Zennaro, M.C., Louiset, E., Lefebvre, H.
  • Journal Title: J. Clin. Endocrinol. Metab. Volume: 100 Issue: 4 Pages: E550-E560
  • DOI: 10.1210/jc.2014-3660
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Primary aldosteronism: functional histopathology and long-term follow-up after unilateral adrenalectomy (2015)
  • Author(s): Volpe, C., Hamberger, B., Hoog, A., Mukai, K., Calissendorff, J., Wahrenberg, H., Zedenius, J., Thoren M.
  • Journal Title: Clin. Endocrinol. (Oxf) Volume: 82 Issue: 5 Pages: 639-647
  • DOI: 10.1111/cen.12645
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A Novel Somatic Deletion Mutation of ATP2B3 in Aldosterone-Producing Adenoma (2015)
  • Author(s): Murakami M, Yoshimoto T, Minami I, Bouchi R, Tsuchiya K, Hashimoto K, Izumiyama H, Fujii Y, Endo T, Akashi T, Nishimoto K, Mukai K, Kihara K, Ogawa Y
  • Journal Title: Endocr Pathol Volume: 26 Issue: 4 Pages: 328-33
  • DOI: 10.1007/s12022-015-9400-9
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Use of plasma metanephrine to aid adrenal venous sampling in combined aldosterone and cortisol over-secretion (2015)
  • Author(s): Goupil, R., Wolley, M., Ungerer, J., McWhinney, B., Mukai, K., Naruse, M., Gordon, R.D., Stowasser, M.
  • Journal Title: Endocrinology, Diabetes and Metabolism Case Rep. Volume: 2015 Pages: 150075-150075
  • DOI: 10.1530/edm-15-0075
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Novel adrenocortical histology and pathology discovered by immunohistochemistry of aldosterone synthase (2015)
  • Author(s): 西本紘嗣郎, 北村 陽典, 中川 健, 関 次男, 小坂 威雄, 大家 基嗣, 笹井 伸哉, 向井 邦晃
  • Journal Title: Official Journal of the Japan Association of Endocrine Surgeons and the Japanese Society of Thyroid Surgery Volume: 32 Issue: 4 Pages: 230-233
  • DOI: 10.11226/jaesjsts.32.4_230
  • NAID: 130005133176
  • ISSN: 2186-9545
  • Open Access
• [Journal Article] Multiple sampling from the central veins with their tributaries can detect bilateral hyperaldosteronism with a cortisol-producing adenoma in a hypertensive patient (2014)
  • Author(s): Sakuma, I., Saito, J., Matsuzawa, Y., Omura, M., Matsui, S., Nishimoto, K., Mukai, K., Nishikawa, T.
  • Journal Title: J. Steroids Horm. Sci. Volume: 5(2) Issue: 02
  • DOI: 10.4172/2157-7536.1000135
  • Peer Reviewed / Open Access
• [Journal Article] Adrenal nodularity and somatic mutations in primary aldosteronism: one node is the culprit? (2014)
  • Author(s): Dekkers, T., ter Meer, M., Lenders, J.W.M., Hermus, A.R.M., L. Schultze Kool, L., Langenhuijsen, J. F., Nishimoto, K., Ogishima, T., Mukai, K., Azizan, E.A.B., Tops, B., Deinum, J., Kusters, B
  • Journal Title: J. Clin. Endocrinol. Metab. Volume: 99 Issue: 7 Pages: E1341-E1351
  • DOI: 10.1210/jc.2013-4255
  • Peer Reviewed
• [Journal Article] 原発性アルドステロン症におけるCYP11B2免疫染色の意義 (2014)
  • Author(s): 西本紘嗣郎、向井邦晃
  • Journal Title: ホルモンと臨床 Volume: 61 Pages: 219-224
• [Presentation] アルドステロン合成酵素の免疫染色によるPAの病理学的確定診断法から病態解明へ (2016)
  • Author(s): 西本紘嗣郎、小山政史、安田政実、西川哲男、向井邦晃
  • Organizer: 第24回日本ステロイドホルモン学会
  • Place of Presentation: ホルトホール大分（大分県大分市）
  • Year and Date: 2016-12-03
  • Invited
• [Presentation] 涙腺における局所ステロイドの生理機能第89回日本生化学会大会 (2016)
  • Author(s): 樋口明弘、山崎岳、向井邦晃、荻島正、前田尚之、横田博
  • Organizer: 第89回日本生化学会大会
  • Place of Presentation: 仙台国際センター（宮城県仙台市）
  • Year and Date: 2016-09-25
  • Int'l Joint Research
• [Presentation] Novel adrenocortical zonation visualized by CYP11B2 immunohistochemistry opens up primary aldosteronism (2016)
  • Author(s): Mukai, K.
  • Organizer: Hypertension Summit 2016
  • Place of Presentation: ホテルグランヴィア京都 (京都府京都市）
  • Year and Date: 2016-05-31
  • Int'l Joint Research / Invited
• [Presentation] アルドステロン(ALDO)産生細胞クラスターからALDO産生腺腫への移行を示唆する新規ALDO過剰産生病変の同定とその体細胞遺伝子変異解析 (2016)
  • Author(s): 西本紘嗣郎、関次男、栗原勲、横田健一、大村昌夫、西川哲男、柴田洋孝、小坂威雄、大家基嗣、末松誠、向井邦晃
  • Organizer: 第104回泌尿器科学会総会
  • Place of Presentation: 仙台国際センター（宮城県仙台市）
  • Year and Date: 2016-04-23
• [Presentation] A novel CYP11B2-specific imaging agent for detection of aldosterone-producing adenomas (2016)
  • Author(s): Abe, T., Naruse, M., Young Jr. W. F., Kobashi, N., Doi, Y., Izawa, A., Akama, K., Okumura, Y., Ikenaga, M., Kimura, H., Saji, H., Mukai, K., Matsumoto, H.
  • Organizer: The 98th Annual Meeting of The Endocrine Society
  • Place of Presentation: ボストン（米国）
  • Year and Date: 2016-04-01
  • Int'l Joint Research
• [Presentation] A Case Report: Nodule Development from Subcapsular Aldosterone-Producing Cell Clusters Causes Hyperaldosteronism (2016)
  • Author(s): Nishimoto, K., Seki, T., Kurihara, I., Yokota, K., Omura, M., Nishikawa, T., Shibata, H., Kosaka, T., Oya, M., Suematsu, M., Mukai, K.
  • Organizer: The 98th Annual Meeting of The Endocrine Society
  • Place of Presentation: ボストン（米国）
  • Year and Date: 2016-04-01
  • Int'l Joint Research
• [Presentation] A novel CYP11B2-specific imaging agent for detection of unilateral subtypes of primary aldosteronism (2016)
  • Author(s): Abe, T., Naruse, M., Young Jr. W. F., Kobashi, N., Doi, Y., Izawa, A., Akama, K., Okumura, Y., Ikenaga, M., Kimura, H., Saji, H., Mukai, K., Matsumoto, H.
  • Organizer: The 41st International Aldosterone Conference 2016
  • Place of Presentation: ボストン（米国）
  • Year and Date: 2016-03-30
  • Int'l Joint Research
• [Presentation] Immuhistochemical analysis of a rare adrenocortical carcinoma causing primary aldosteronism and subclinical Cushing’s syndrome demonstrating disorganized expression pattern of steroidogenic enzymes (2016)
  • Author(s): Uchida, T., Nishimoto, K., Goto, H., Kawano, Y., Shimizu, F., Asahina M., Fukumura Y., Tsujimura, A., Mukai, K., Suematsu, M., Gomez-Sanchez, C. E., Yao, T., Horie, S., Watada, H.
  • Organizer: The 41st International Aldosterone Conference 2016
  • Place of Presentation: ボストン（米国）
  • Year and Date: 2016-03-30
  • Int'l Joint Research
• [Presentation] A NOVEL TYPE OF JUVENILE PRIMARY ALDOSTERONISM DUE TO A KCNJ5 SOMATIC MUTATION THAT PRESUMABLY OCCURRED IN AN ADRENOCORTICAL PRECURSOR CELL (2016)
  • Author(s): Tamura, A., Nishimoto, K., Seki, T., Matsuzawa, Y., Saito, J., Omura, M., Gomez-Sanchez, C. E., Makita, K., Matsui, S., Moriya, N., Inoue, A., Nagata, M., Sasano, H., Nakamura, Y., Yamazaki, Y., Suematsu, M., Mukai, K., Kosaka, T., Oya, M., Suematsu, S., Nishikawa, T.
  • Organizer: The 27th Conference on the Adrenal Cortex
  • Place of Presentation: ボストン（米国）
  • Year and Date: 2016-03-29
  • Int'l Joint Research
• [Presentation] A novel pathology related to subcapsular aldosterone-producing cell clusters causes hyperaldosteronism (2016)
  • Author(s): Nishimoto, K., Seki, T., Kurihara, I., Yokota, K., Omura, M., Nishikawa, T., Shibata, H., Kosaka, T., Oya, M., Suematsu, M., Mukai, K.
  • Organizer: The 101st American Urological Association Annual Meeting
  • Place of Presentation: サンディエゴ（米国）
  • Year and Date: 2016-03-06
  • Int'l Joint Research
• [Presentation] ヒト大腸がん肝転移病巣のin vivo細胞周期依存的エネルギー代謝を質量分析イメージングで可視化する (2015)
  • Author(s): 久保-弓場 亜紀子、鮑 彦、向井 邦晃、菱木 貴子、大村 光代、南嶋 洋司、末松 誠
  • Organizer: BMB2015[第38回日本分子生物学会年会、第88回日本生化学会大会 合同大会]
  • Place of Presentation: 神戸国際会議場（兵庫県神戸市）
  • Year and Date: 2015-12-01
• [Presentation] 涙腺における局所ステロイドの生理機能 (2015)
  • Author(s): 樋口明弘、山崎 岳、向井邦晃、荻島 正、前田尚之、横田 博、坪田一男
  • Organizer: BMB2015[第38回日本分子生物学会年会、第88回日本生化学会大会 合同大会]
  • Place of Presentation: 神戸国際会議場（兵庫県神戸市）
  • Year and Date: 2015-12-01
• [Presentation] ヒト副腎皮質の構成的アルドステロン産生細胞クラスターに生じる体細胞変異の解析 (2015)
  • Author(s): 向井邦晃、荻島 正、樋口明弘、西本紘嗣郎
  • Organizer: BMB2015[第38回日本分子生物学会年会、第88回日本生化学会大会 合同大会]
  • Place of Presentation: 神戸国際会議場（兵庫県神戸市）
  • Year and Date: 2015-12-01
• [Presentation] A novel CYP11B2-specific positron emission tomography imaging agent for detection of aldosterone-producing adenomas (2015)
  • Author(s): Abe, T., Naruse, M., Young Jr. W. F., Kobashi, N., Doi, Y., Izawa, A., Akama, K., Okumura, Y., Ikenaga, M., Kimura, H., Saji, H., Mukai, K., Matsumoto, H.
  • Organizer: European network for study of adrenal tumor
  • Place of Presentation: ミュンヘン（ドイツ）
  • Year and Date: 2015-11-19
  • Int'l Joint Research
• [Presentation] β細胞ストレスに応答する膵島ノンシステミックステロイド合成 (2015)
  • Author(s): 荻島正、堤かおり、中村祐貴、前田尚之、向井邦晃、樋口明弘
  • Organizer: 第87回日本生化学会
  • Place of Presentation: 国立京都国際会館（京都府・京都市）
  • Year and Date: 2015-10-15 – 2015-10-18
• [Presentation] 涙腺における局所ステロイドの生理機能 (2015)
  • Author(s): 樋口明弘、山崎岳、向井邦晃、荻島正、前田尚之、横田博、坪田一男
  • Organizer: 第87回日本生化学会
  • Place of Presentation: 国立京都国際会館（京都府・京都市）
  • Year and Date: 2015-10-15 – 2015-10-18
• [Presentation] アルドステロン合成酵素免疫染色と次世代シーケンサーによるアルドステロン産生腺腫の発生母地の解明 (2015)
  • Author(s): 西本紘嗣郎、小坂威雄、大家基嗣、向井邦晃
  • Organizer: 第27回内分泌外科学会総会
  • Place of Presentation: コラッセふくしま（福島県・福島市）
  • Year and Date: 2015-05-28 – 2015-05-29
• [Presentation] アルドステロン合成酵素免疫染色と次世代シーケンサーによるアルドステロン産生腺腫の発生母地の解明 (2015)
  • Author(s): 西本紘嗣郎、小坂威雄、大家基嗣、向井邦晃
  • Organizer: 第27回内分泌外科学会総会
  • Place of Presentation: コラッセふくしま（福島県福島市）
  • Year and Date: 2015-05-28
• [Presentation] ヒトにおける11-ケトテストステロンの合成と役割 (2015)
  • Author(s): 今道力敬、矢澤隆志、河邉真也、石兼真、向井邦晃、折坂誠、水谷哲也、宮本薫
  • Organizer: 第88回日本内分泌学会学術総会
  • Place of Presentation: ホテルニューオータニ東京（東京都・千代田区）
  • Year and Date: 2015-04-23 – 2015-04-25
• [Presentation] 原発性アルドステロン症及びサブクリニカルクッシング症候群を呈する副腎皮質癌の１例 (2015)
  • Author(s): 河野結衣、内田豊義、清水史孝、朝比奈未紀、西本紘嗣郎、向井邦晃、八尾隆史、堀江重郎、綿田裕孝
  • Organizer: 第88回日本内分泌学会学術総会
  • Place of Presentation: ホテルニューオータニ東京（東京都・千代田区）
  • Year and Date: 2015-04-23 – 2015-04-25
• [Presentation] 原発性アルドステロン症及びサブクリニカルクッシング症候群を呈する副腎皮質癌の１例 (2015)
  • Author(s): 河野結衣、内田豊義、清水史孝、朝比奈未紀、西本紘嗣郎、向井邦晃、八尾隆史、堀江重郎、綿田裕孝
  • Organizer: 第88回日本内分泌学会学術集会
  • Place of Presentation: ホテルニューオータニ東京（東京都千代田区）
  • Year and Date: 2015-04-23
• [Presentation] ヒトにおける11-ケトテストステロンの合成と役割 (2015)
  • Author(s): 今道力敬、矢澤隆志、河邉真也、石兼真、向井邦晃、折坂誠、水谷哲也、宮本薫
  • Organizer: 第88回日本内分泌学会学術集会
  • Place of Presentation: ホテルニューオータニ東京（東京都千代田区）
  • Year and Date: 2015-04-23
• [Presentation] Immunohistochemical analysis of cortisol and aldosterone secreting adrenocortical carcinoma (2015)
  • Author(s): Murakami, M., Yoshimoto, T., Komatsu, N., Nakano, Y., Minami, I., Mihara, M., Izumiyama, H., Hashimoto, K., Ban, D., Ochiai, T., Takemoto, A., Yukimori, A, Nakajima, H., Akashi, T., Homma, K., Nishimoto, K., Mukai, K., Hasegawa, T., Tanabe, M., Ogawa, Y.
  • Organizer: The 97th Annual Meeting of The Endocrine Society
  • Place of Presentation: 米国・サンディエゴ市
  • Year and Date: 2015-03-05 – 2015-03-08
• [Presentation] 11-ケトテストステロンはエストロゲン変換を受けないアンドロゲンとして機能する (2015)
  • Author(s): 今道力敬、矢澤隆志、河邉真也、石兼真、向井邦晃、折坂誠、水谷哲也、宮本薫
  • Organizer: 第19回生殖内分泌学会
  • Place of Presentation: 千里ライフサイエンスセンター（大阪府・豊中市）
  • Year and Date: 2015-01-10
• [Book] 原発性アルドステ口ン症診療マニュアル 改訂第3版 (2017)
  • Author(s): 西本紘嗣郎, 安田政実, 向井邦晃（編集者 成瀬光栄、平田結喜緒、田辺晶代）
  • Total Pages: 195
  • Publisher: 診断と治療社