The elucidation of the mechanism to regulate ATP signaling of bladder in upper central nervous system

• Project/Area Number: 17K16791
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Urology
• Research Institution: Osaka University
• Principal Investigator: Ueda Norichika 大阪大学, 医学部附属病院, 医員 (40759528)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2018: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: ATP / 脊髄c-Fos / 膀胱 / 脊髄L6 / c-Fos / 膀胱ATPシグナル

Outline of Final Research Achievements

In this study, we performed intravesical ATP instillation in the mouse bladder. We evaluated urinary function with novel reliable methods using improved cystometry and ultrasonography, which we previously established. We found that intravesical ATP instillation induced the decrease of intercontraction intervals and the increase of c-Fos positive cells. To confirm that c-Fos expression in the L6 spinal cord was induced by neural signaling of primary bladder afferent nerves, we injected CTB into the bladder and performed c-Fos immunostaining. CTB-positive nerves appeared to converge at the deep layer in the L6 spinal cord where almost all c-Fos-positive cells were located. Additionally, CTB-positive nerves appeared to connect directly to c-Fos-positive cells.

Academic Significance and Societal Importance of the Research Achievements

膀胱内腔のATPが発生させる神経シグナルは、膀胱求心性神経を活性化させて排尿反射を亢進し、頻尿をきたすことが明らかとなった。過活動膀胱患者の尿中ATP濃度は健常者と比較し高値であることが報告されており、本研究結果を踏まえると、膀胱内腔のATPが頻尿症状に関与している可能性が示唆される。以上より、膀胱内腔のATPを制御することが過活動膀胱などの尿中ATPが増加する頻尿疾患の新規治療法になる可能性が示唆された。

Research Products

• [Journal Article] Intravesical ATP instillation induces urinary frequency because of activation of bladder afferent nerves without inflammatory changes in mice: A promising model for overactive bladder. (2018)
  • Author(s): Ueda N, Kondo M, Takezawa K, Kiuchi H, Sekii Y, Inagaki Y, Soda T, Fukuhara S, Fujita K, Uemura M, Imamura R, Miyagawa Y, Nonomura N, Shimada S.
  • Journal Title: Biochem Biophys Res Commun Volume: 506 Issue: 3 Pages: 498-503
  • DOI: 10.1016/j.bbrc.2018.10.106
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Bladder urothelium triggers an immediate defensive response against bacterial lipopolysaccharide via ATP signaling (2018)
  • Author(s): Norichika Ueda, Makoto Kondo, Hiroshi Kiuchi, Yusuke Inagaki, Kentaro Takezawa, Shinichiro Fukuhara, Shoichi Shimada, Norio Nonomura
  • Organizer: American Urological Association
  • Int'l Joint Research