Sleep apnea syndrome induces clock gene abnormalities and causes nocturia in the mice bladder

• Project/Area Number: 19K18579
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 56030:Urology-related
• Research Institution: University of Yamanashi
• Principal Investigator: IHARA Tatsuya 山梨大学, 大学院総合研究部, 助教 (90622407)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
• Keywords: 夜間頻尿 / 睡眠時無呼吸症候群 / 時計遺伝子 / 概日リズム障害 / 低酸素ストレス

Outline of Research at the Start

・マウス膀胱上皮培養細胞、膀胱平滑筋培養細胞、膀胱ex vivoカルチャー組織における時計遺伝子発現変化と、低酸素によって誘導される各種タンパク、酵素類の概日リズムを測定し、時計遺伝子リズム異常との関連を調べる。
・上記組織に低酸素刺激を負荷し、誘発される概日リズム障害を調べる。
・夜間頻尿モデルである時計遺伝子変異マウス(Clock mutantマウス)を用い、上記で得られた結果とClock mutantマウスの結果を比較する。
・時計遺伝子代謝に作用する薬剤投与による膀胱の時計遺伝子リズム改善作用を確認する。
・骨盤内低酸素モデルのラットを用い、生体外で得られた実験結果と比較する。

Outline of Final Research Achievements

SAS loading increased the frequency of mouse voiding during sleep. In addition, bladder capacity also decreased after SAS loading. These results indicated that SAS could induces nocturia-like pathology in mice. As for the clock gene Per2 expression rhythm in cultured cells of bladder epithelium after hypoxic stimulation, a circadian rhythm similar to that of control was observed with 10% hypoxic stimulation. However, the circadian rhythm changed as the oxygen concentration was lowered to 5% and 1%. The circadian Per2 expression disappeared completely with 1% hypoxic stimulation. From these results, SAS loading may cause nocturia through abnormal circadian rhythm of the bladder.

Academic Significance and Societal Importance of the Research Achievements

SSASの慢性的な低酸素ストレスが膀胱の時計遺伝子異常を介し夜間頻尿を惹起させる。いままで言われてこなかった新しい病態の一つであり、夜間頻尿に対する新規の治療戦略、新規治療薬の創生に結び付く可能性がある。

Research Products

• [Journal Article] Different effects of GsMTx4 on nocturia associated with the circadian clock and Piezo1 expression in mice (2021)
  • Author(s): Tatsuya Ihara, Takahiko Mitsui, Hiroshi Shimura, SachikoTsuchiya, Mie Kanda, Satoru Kira, Hiroshi Nakagomi, Norifumi Sawada, Manabu Kamiyama, Eiji Shigetomi, Yoichi Shinozaki, Schuichi Koizumi, Masayuki Takeda
  • Journal Title: Life Sciences Volume: 278 Pages: 119555-119555
  • DOI: 10.1016/j.lfs.2021.119555
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Intermittent restraint stress induces circadian misalignment in the mouse bladder, leading to nocturia. (2019)
  • Author(s): Ihara T, Nakamura Y, Mitsui T, Tsuchiya S, Kanda M, Kira S, Nakagomi H, Sawada N, Kamiyama M, Shigetomi E, Shinozaki Y, Yoshiyama M, Nakao A, Koizumi S, Takeda M.
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 10069-10069
  • DOI: 10.1038/s41598-019-46517-w
  • Peer Reviewed / Open Access / Int'l Joint Research