Elucidation and clinical application of a novel method for preventing urolithiasis focusing on the antioxidant effect of estrogen

• Project/Area Number: 17K11189
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Urology
• Research Institution: Nagoya City University
• Principal Investigator: Hirose Masahito 名古屋市立大学, 医薬学総合研究院(医学), 研究員 (70529172)
• Co-Investigator(Kenkyū-buntansha): 安井 孝周 名古屋市立大学, 医薬学総合研究院(医学), 教授 (40326153) ; 岡田 淳志 名古屋市立大学, 医薬学総合研究院(医学), 准教授 (70444966) ; 濱本 周造 名古屋市立大学, 医薬学総合研究院(医学), 講師 (80551267) ; 海野 怜 名古屋市立大学, 医薬学総合研究院(医学), 研究員 (40755683) ; 田口 和己 名古屋市立大学, 医薬学総合研究院(医学), 助教 (00595184) ; 戸澤 啓一 名古屋市立大学, 医薬学総合研究院(医学), 教授 (40264733) ; 郡 健二郎 名古屋市立大学, その他部局等, 学長 (30122047)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: 尿路結石 / エストロゲン / 酸化ストレス / オートファジー / 褐色脂肪細胞 / Randall's plaque / ゲノムワイド解析 / N-acetyl-L-Cysteine / mTOR / 細胞傷害 / ベージュ細胞 / 褐色脂肪組織 / ミトコンドリア傷害 / 結石モデルマウス / 網羅的発現解析 / 細胞障害 / ミトコンドリア / オステオポンチン

Outline of Final Research Achievements

The aim of this study was to investigate the preventive effect of estrogen on the urinary stone formation. However, but it was reported that "the cytotoxic effect of estrogen" and "the difference in adipose tissue composition between men and women". Based on this change of the basic concept, the following research was conducted. (1) Observation of autophagy in renal cell injury due to renal stone formation, and stone preventive effect by enhancing autophagy of antioxidant N-acetyl-L-Cysteine (NAC) that suppresses bone mineral loss due to estrogen deficiency (ovarian resection), (2) Stone-suppressing effect of brown adipose tissue and beige cells, and (3) Genome-wide analysis of estrogen-related genes in human kidney tissue were performed.
As a result, (1) administration of NAC, (2) induction of brown adipocytes suppressed stone formation, and (3) abnormalities of estrogen receptor and androgen metabolism were observed in human renal tissue.

Academic Significance and Societal Importance of the Research Achievements

本研究は、当初予定していた直接的なエストロゲン投与ではなく、女性の褐色細胞活性の優位性と抗酸化ストレスによるオートファジーの亢進に着眼した研究に移行し、それぞれに結果を得た。この成果は尿生化学のみを中心に評価される尿路結石予防に一石を投じるものであり、学術的意義議が高い。
加えて、本邦の尿路結石の男女比はこの40年間 2.5:1であったが、2015年には2.2:1となり、欧米の男女比(1:1)に近づきつつある。本研究の成果はその基礎的な背景を現す可能性があり、「本来は女性が結石になりにくい」というメカニズムを詳細に紐解くことで新たな予防法の創出につながる社会的意義もある成果であった。

Research Products

• [Journal Article] Fatty acid?binding protein 4 downregulation drives calcification in the development of kidney stone disease (2020)
  • Author(s): Taguchi Kazumi、Chen Ling、Usawachintachit Manint、Hamamoto Shuzo、Kang Misun、Sugino Teruaki、Unno Rei、Tzou David T.、Sherer Benjamin A.、Okada Atsushi、Yasui Takahiro、Ho Sunita P.、Stoller Marshall L.、Chi Thomas
  • Journal Title: Kidney International Volume: - Issue: 5 Pages: 1042-1056
  • DOI: 10.1016/j.kint.2020.01.042
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Deregulated MTOR (mechanistic target of rapamycin kinase) is responsible for autophagy defects exacerbating kidney stone development (2019)
  • Author(s): Unno Rei, Kawabata Tsuyoshi, Taguchi Kazumi, Sugino Teruaki, Hamamoto Shuzo, Ando Ryosuke, Okada Atsushi, Kohri Kenjiro, Yoshimori Tamotsu, Yasui Takahiro
  • Journal Title: Autophagy Volume: E-pub Issue: 4 Pages: 709-723
  • DOI: 10.1080/15548627.2019.1635382
  • Peer Reviewed / Open Access
• [Journal Article] Brown adipocytes and β3-stimulant-induced brown-like adipocytes contribute to the prevention of renal crystal formation (2019)
  • Author(s): Sugino Teruaki, Okada Atsushi, Taguchi Kazumi, Unno Rei, Hamamoto Shuzo, Ando Ryosuke, Mogami Tohru, Kohri Kenjiro, Yamashita Hitoshi, Yasui Takahiro
  • Journal Title: American Journal of Physiology. Renal Physiology Volume: 316 Issue: 6 Pages: 1282-1282
  • DOI: 10.1152/ajprenal.00523.2018
  • Peer Reviewed
• [Journal Article] Helper T-cell signaling and inflammatory pathway lead to formation of calcium phosphate but not calcium oxalate stones on Randall's plaques. (2019)
  • Author(s): Taguchi K, Hamamoto S, Okada A, Sugino T, Unno R, Ando R, Gao B, Tozawa K, Kohri K, Yasui T
  • Journal Title: Int J Urol Volume: - Issue: 6 Pages: 670-677
  • DOI: 10.1111/iju.13950
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Active phagocytosis and diachronic processing of calcium oxalate monohydrate crystals in an in vitro macrophage model (2019)
  • Author(s): Okada Atsushi, Aoki Hiromasa, Onozato Daichi, Kato Taiki, Hashita Tadahiro, Takase Hiroshi, Sugino Teruaki, Unno Rei, Taguchi Kazumi, Hamamoto Shuzo, Ando Ryosuke, Mizuno Kentaro, Tozawa Keiichi, Matsunaga Tamihide, Kohri Kenjiro, Yasui Takahiro
  • Journal Title: Kidney and Blood Pressure Research Volume: 44 Issue: 5 Pages: 1014-1014
  • DOI: 10.1159/000501965
  • Peer Reviewed / Open Access
• [Journal Article] Feasibility of metronomic chemotherapy with tegafur-uracil, cisplatin, and dexamethasone for docetaxel-refractory prostate cancer (2017)
  • Author(s): Kubota Hiroki、Fukuta Katsuhiro、Yamada Kenji、Hirose Masahito、Naruyama Hiromichi、Yanai Yoshimasa、Yamada Yasuyuki、Watase Hideki、Kawai Noriyasu、Tozawa Keiichi、Yasui Takahiro
  • Journal Title: Journal of Rural Medicine Volume: 12 Issue: 2 Pages: 112-119
  • DOI: 10.2185/jrm.2938
  • NAID: 130006233707
  • ISSN: 1880-487X, 1880-4888
  • Peer Reviewed
• [Presentation] 開業医の立場での結石治療（指導医教育コース2 シンポジウム3） (2019)
  • Author(s): 広瀬真仁
  • Organizer: 第69回日本泌尿器科学会中部総会
  • Invited
• [Presentation] 腹腔鏡下膀胱全摘除術の術後再発症例の検討 (2017)
  • Author(s): 永田 大介、池上 要介、太田 裕也、丸山 哲史、広瀬 真仁、阪野 里花、坂倉 毅、藤井 泰普、安井 孝周
  • Organizer: 第105回日本泌尿器科学会総会
• [Presentation] 後腹膜血腫を併発した急性前立腺炎の1例 (2017)
  • Author(s): 岡田 朋記、阪野 里花、永田 大介、坂倉 毅、浅井 希彦、坂東 勇弥、犬飼 遼、鈴木 啓史、広瀬 真仁
  • Organizer: 第276回日本泌尿器科学会東海地方会