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rCountermeasures for nocturnal polyuria tageting renal aquaporin molecule

Research Project

Project/Area Number 20K09521
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 56030:Urology-related
Research InstitutionUniversity of Fukui

Principal Investigator

Yokoyama Osamu  福井大学, 学術研究院医学系部門, 名誉教授 (90242552)

Co-Investigator(Kenkyū-buntansha) 伊藤 秀明  福井大学, 学術研究院医学系部門, 准教授 (00345620)
小林 基弘  福井大学, 学術研究院医学系部門, 教授 (00362137)
多賀 峰克  福井大学, 学術研究院医学系部門(附属病院部), 講師 (00529349)
青木 芳隆  福井大学, 学術研究院医学系部門(附属病院部), 講師 (30273006)
大江 秀樹  福井大学, 学術研究院医学系部門(附属病院部), 医員 (70760510)
Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2022: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2021: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2020: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
Keywords夜間多尿 / 夜間頻尿 / 抗コリン薬 / アクアポリン分子 / デスモプレシン / cAMP / 腎皮質集合管 / 腎集合管 / アクアポリン2 / ナトリウム / バソプレッシン / ラット / 抗利尿 / 腎
Outline of Research at the Start

夜間多尿に起因する夜間頻尿は難治である。2019年デスモプレシン製剤が上市され夜間多尿の治療選択肢が広がったが、適応が男性のみで高齢者では低ナトリウム血症のリスクも高い。われわれは眠前の睡眠薬・抗コリン薬、α遮断薬が夜間多尿を改善し尿産生リズムを夜から昼型へ戻す可能性を報告した。準備実験でも抗コリン薬が腎尿細管~集合管に作用し、尿が再吸収される可能性が示唆される結果が得られた。アクアポリン(AQP)は細胞膜を通して水分子を移動させる。腎にはAQP1、2、3、4、6、7、11 が存在するがAQP2あるいはAQP6が抗利尿の責任分子ではないかと仮説を立て、疑問を解き明かす研究を計画した。

Outline of Final Research Achievements

Experiments were conducted to determine whether the decrease in urine volume by anticholinergics is due to reabsorption in the bladder or kidney. Saline and glucose solutions were absorbed from the rat bladder, however, there was no difference in reabsorption between with or without anticholinergics. For renal absorption, urinary AQP2 protein measurement, fluorescence immunostaining of AQP2 and cAMP measurement of the kidney were performed. Under diuretic conditions, AQP2 molecules were distributed within the collecting duct cytoplasm in the renal cortex. Anticholinergics and desmopressin suppressed urine production, increased the intracellular cAMP levels and caused the AQP2 molecule to localize to the collecting duct cells' luminal side. The urinary reabsorption mechanism through the bladder epithelium was not activated by anticholinergics. Thus, anticholinergics suppress urine production via an increase in urine reabsorption in the kidneys' collecting duct cells via AQP2.

Academic Significance and Societal Importance of the Research Achievements

膀胱はこれまで尿の代謝に影響を与えないと考えられていたが、機能的膀胱容量に達するとヒトの膀胱で水吸収が生じる。本研究でも膀胱上皮を介する尿吸収メカニズムが存在することを示した。しかし、抗コリン薬による膀胱での尿吸収促進は否定的で、抗コリン薬は腎皮質集合管のcAMP上昇、AQP2分子の管腔測への移動を介して抗利尿に働く可能性があること、Na+などの電解質も再吸収される可能性があることを初めて報告した。臨床的にも短時間作用型抗コリン薬が夜間尿量を減少させることが報告されているが、抗コリン薬が尿量減少をもたらす機序として腎皮質集合管でAQP2が関与していることを初めて証明した。

Report

(4 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • Research Products

    (16 results)

All 2022 2021 2020

All Journal Article (11 results) (of which Peer Reviewed: 10 results,  Open Access: 7 results) Presentation (4 results) (of which Invited: 2 results) Book (1 results)

  • [Journal Article] Phosphodiesterase 5 inhibitor suppresses prostate weight increase in type 2 diabetic rats2022

    • Author(s)
      Kobayashi Hisato、Zha Xinmin、Nagase Keiko、Inamura So、Taga Minekatsu、Aoki Yoshitaka、Ito Hideaki、Yokoyama Osamu
    • Journal Title

      Life Sciences

      Volume: 298 Pages: 120504-120504

    • DOI

      10.1016/j.lfs.2022.120504

    • Related Report
      2022 Annual Research Report
  • [Journal Article] Urinary reabsorption in the rat kidney by anticholinergics2021

    • Author(s)
      Hideki Oe*, Hatsumi Yoshiki, Xinmin Zha, Hisato Kobayashi, Yoshitaka Aoki, Hideaki Ito & Osamu Yokoyama
    • Journal Title

      Scientific reports

      Volume: 11 Issue: 1 Pages: 9191-9191

    • DOI

      10.1038/s41598-021-88738-y

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Expression of functional E-selectin ligands on the plasma membrane of carcinoma cells correlates with poor prognosis in clear cell renal cell carcinoma.2021

    • Author(s)
      Tanio M, Muramoto A, Hoshino H, Murahashi M, Imamura Y, Yokoyama O, Kobayashi M.
    • Journal Title

      Urol Oncol.

      Volume: 39 Issue: 5 Pages: 302.e9-302.e18

    • DOI

      10.1016/j.urolonc.2021.02.013

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Clinical Guidelines for Female Lower Urinary Tract Symptoms (second edition).2021

    • Author(s)
      Takahashi S, Takei M, Asakura H, Gotoh M, Ishizuka O, Kato K, Koyama M, Takeyama M, Tomoe H, Yamanishi T, Yokoyama O, Yoshida M, Yoshimura Y, Yoshizawa T.
    • Journal Title

      Int J Urol.

      Volume: 28 Issue: 5 Pages: 474-492

    • DOI

      10.1111/iju.14492

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Adrenal pheochromocytoma treated by combination of adrenal arterial embolization and radiofrequency ablation2021

    • Author(s)
      Kako Yasukazu、Ueki Ryusuke、Yamamoto Shingo、Takaki Haruyuki、Aoki Yoshitaka、Yokoyama Osamu、Yamakado Koichiro
    • Journal Title

      Clinical Case Reports

      Volume: 9 Issue: 3 Pages: 1261-1265

    • DOI

      10.1002/ccr3.3745

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Impact of Medical Castration on Malignant Arrhythmias in Patients With Prostate Cancer.2021

    • Author(s)
      Hasegawa K, Ito H, Kaseno K, Miyazaki S, Shiomi Y, Tama N, Ikeda H, Ishida K, Uzui H, Ohno S, Horie M, Yokoyama O, Tada H.
    • Journal Title

      J Am Heart Assoc.

      Volume: 10 Issue: 5

    • DOI

      10.1161/jaha.120.017267

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Efficacy and safety of the noradrenaline reuptake inhibitor, TAS-303, in women with stress urinary incontinence: Results of a double-blind, randomized, placebo-controlled, early phase II trial.2021

    • Author(s)
      Takahashi S, Kato K, Takei M, Yokoyama O, Gotoh M.
    • Journal Title

      Int J Urol.

      Volume: 28 Issue: 1 Pages: 82-90

    • DOI

      10.1111/iju.14411

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Duration of smoking cessation is negatively associated with the magnitude of chronic prostatic inflammation and storage dysfunction in patients with benign prostatic hyperplasia.2020

    • Author(s)
      Inamura S, Ito H, Oe H, Seki M, Taga M, Kobayashi M, Yokoyama O.
    • Journal Title

      Int J Urol.

      Volume: 27 Issue: 10 Pages: 874-881

    • DOI

      10.1111/iju.14320

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Correcting imbalance of sex hormones by a phosphodiesterase 5 inhibitor improves copulatory dysfunction in male rats with type 2 diabetes.2020

    • Author(s)
      Itoga A, Zha X, Nagase K, Aoki Y, Ito H and Osamu Yokoyama.
    • Journal Title

      BMJ Open Diabetes Res Care.

      Volume: 8 Issue: 1 Pages: e001111-e001111

    • DOI

      10.1136/bmjdrc-2019-001111

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Efficacy of vibegron, a novel β3-adrenoreceptor agonist, on severe urgency urinary incontinence related to overactive bladder: post hoc analysis of a randomized, placebo-controlled, double-blind, comparative phase 3 study.2020

    • Author(s)
      Yoshida M, Takeda M, Gotoh M, Yokoyama O, Kakizaki H, Takahashi S, Masumori N, Nagai S, Minemura K.
    • Journal Title

      BJU Int.

      Volume: 125 Issue: 5 Pages: 709-717

    • DOI

      10.1111/bju.15020

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] OnabotulinumtoxinA (botulinum toxin type A) for the treatment of Japanese patients with overactive bladder and urinary incontinence: Results of single-dose treatment from a phase III, randomized, double-blind, placebo-controlled trial (interim analysis).2020

    • Author(s)
      Yokoyama O, Honda M, Yamanishi T, Sekiguchi Y, Fujii K, Nakayama T, Mogi T.
    • Journal Title

      Int J Urol

      Volume: 27 Issue: 3 Pages: 227-234

    • DOI

      10.1111/iju.14176

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] 夜間多尿を中心とした夜間頻尿の診断と治療2021

    • Author(s)
      横山修
    • Organizer
      第86回日本泌尿器科学会東部総会
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] ラット腎臓における抗コリン薬を介した尿再吸収に関する検討2021

    • Author(s)
      大江秀樹 吉木はつみ 査新民 小林久人 福島正人 青木芳隆
    • Organizer
      第24回北陸BRM研究会
    • Related Report
      2020 Research-status Report
  • [Presentation] ラット腎臓における抗コリン薬を介した尿再吸収に関する検討2020

    • Author(s)
      大江秀樹 吉木はつみ 査新民 小林久人 福島正人 青木芳隆伊藤秀明 横山修
    • Organizer
      第108回日本泌尿器科学会総会
    • Related Report
      2020 Research-status Report
  • [Presentation] Nocturia協奏曲~夜間頻尿・多尿を多面的に考える~2020

    • Author(s)
      横山修
    • Organizer
      第27回日本排尿機能学会
    • Related Report
      2020 Research-status Report
    • Invited
  • [Book] 夜間頻尿診療ガイドライン(第2版)2020

    • Author(s)
      吉田正貴、横山修 他
    • Total Pages
      178
    • Publisher
      リッチヒルメディカル
    • Related Report
      2020 Research-status Report

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Published: 2020-04-28   Modified: 2024-01-30  

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