lancet-header
Preprints with The Lancet is part of SSRN´s First Look, a place where journals and other research experts identify content of interest prior to publication. These preprint papers are not peer-reviewed. Authors have either opted in at submission to The Lancet family of journals to post their preprints on Preprints with The Lancet, or submitted directly via SSRN. The usual SSRN checks and a Lancet-specific check for appropriateness and transparency have been applied. These papers should not be used for clinical decision making or reporting of research to a lay audience without indicating that this is preliminary research that has not been peer-reviewed. For more information see the Comment published in The Lancet, or visit The Lancet´s FAQ page, and for any feedback please contact preprints@lancet.com

Intermittent Restraint Stress Induces Circadian Misalignment in the Mouse Bladder, Leading to Nocturia

42 Pages Posted: 13 Apr 2019

See all articles by Tatsuya Ihara

Tatsuya Ihara

University of Yamanashi - Department of Urology

Yuki Nakamura

University of Yamanashi - Interdisciplinary Graduate School of Medicine

Takahiko Mitsui

University of Yamanashi - Department of Urology

Sachiko Tsuchiya

University of Yamanashi - Department of Urology

Mie Kanda

University of Yamanashi - Department of Urology

Satoru Kira

University of Yamanashi - Department of Urology

Hiroshi Nakagomi

University of Yamanashi - Department of Urology

Norifumi Sawada

University of Yamanashi - Department of Urology

Manabu Kamiyama

University of Yamanashi - Department of Urology

Eiji Shigetomi

University of Yamanashi - Interdisciplinary Graduate School of Medicine

Yoichi Shinozaki

University of Yamanashi - Interdisciplinary Graduate School of Medicine

Mitsuharu Yoshiyama

University of Yamanashi - Department of Urology

Atsuhito Nakao

University of Yamanashi - Interdisciplinary Graduate School of Medicine

Schuichi Koizumi

University of Yamanashi - Interdisciplinary Graduate School of Medicine

Masayuki Takeda

University of Yamanashi - Department of Urology

More...

Abstract

Background: Intermittent stress disrupts the circadian rhythm in clock genes such as Per2 only in peripheral organs without any effect on the central nervous system. Here, the effect of restraint stress (RS) on circadian bladder function was investigated based on urination behavior and gene expression rhythms. Furthermore, PF670462 (PF), a Per2 phosphorylation enzyme inhibitor, was administered to investigate the effects on circadian bladder re-alignment after RS.

Method: Two-hour RS during the light phase was applied to mice (RS mice) for 5 days. The following parameters were then examined: urination behaviors; clock gene expression rhythms and urinary sensory-related molecules; Per2 expression in the excised bladder of Per2::luc mice; in vivo Per2 expression rhythms in the bladder of Per2::luc mice.

Findings: Control mice did not show altered urination behavior in the light phase, whereas RS mice exhibited a higher voiding frequency and lower bladder capacity. In the bladder mucosa, RS mice also showed abrogated or misaligned urinary sensory-related molecules and clock gene expression. The rhythmic expression of Per2 was also altered in RS mice both in excised- and in vivo bladder, compared with control mice. After PF administration, voiding frequency was reduced and bladder capacity was increased during the light phase in RS mice; the in vivo Per2 expression rhythm was also fully restored.

Interpretation: RS can alter circadian gene expression in the bladder during the light phase and might cause nocturia via changes in circadian bladder function due the dysregulation of clock genes. Amending the circadian rhythm therapeutically could be applied for nocturia.

Funding Statement: This work was supported financially by Suzuki Urinary Medicine Promotion Foundation and Astellas Pharma Inc.

Declaration of Interests: The authors declare that they have no conflicts of interest with the contents of this article.

Ethics Approval Statement: All procedures were conducted in accordance with the Guiding Principles in the Care and Use of Animals in the Field of the Physiologic Society of Japan and the policies of the Institutional Animal Care and Use Committee.

Keywords: circadian bladder function; circadian rhythm; clock genes; nocturia; Per2; restrain stress

Suggested Citation

Ihara, Tatsuya and Nakamura, Yuki and Mitsui, Takahiko and Tsuchiya, Sachiko and Kanda, Mie and Kira, Satoru and Nakagomi, Hiroshi and Sawada, Norifumi and Kamiyama, Manabu and Shigetomi, Eiji and Shinozaki, Yoichi and Yoshiyama, Mitsuharu and Nakao, Atsuhito and Koizumi, Schuichi and Takeda, Masayuki, Intermittent Restraint Stress Induces Circadian Misalignment in the Mouse Bladder, Leading to Nocturia (April 10, 2019). Available at SSRN: https://ssrn.com/abstract=3369756 or http://dx.doi.org/10.2139/ssrn.3369756

Tatsuya Ihara

University of Yamanashi - Department of Urology ( email )

Yamanashi
Japan

Yuki Nakamura

University of Yamanashi - Interdisciplinary Graduate School of Medicine

Yamanashi
Japan

Takahiko Mitsui (Contact Author)

University of Yamanashi - Department of Urology ( email )

Yamanashi
Japan

Sachiko Tsuchiya

University of Yamanashi - Department of Urology

Yamanashi
Japan

Mie Kanda

University of Yamanashi - Department of Urology

Yamanashi
Japan

Satoru Kira

University of Yamanashi - Department of Urology

Yamanashi
Japan

Hiroshi Nakagomi

University of Yamanashi - Department of Urology

Yamanashi
Japan

Norifumi Sawada

University of Yamanashi - Department of Urology

Yamanashi
Japan

Manabu Kamiyama

University of Yamanashi - Department of Urology

Yamanashi
Japan

Eiji Shigetomi

University of Yamanashi - Interdisciplinary Graduate School of Medicine

Yamanashi
Japan

Yoichi Shinozaki

University of Yamanashi - Interdisciplinary Graduate School of Medicine

Yamanashi
Japan

Mitsuharu Yoshiyama

University of Yamanashi - Department of Urology

Yamanashi
Japan

Atsuhito Nakao

University of Yamanashi - Interdisciplinary Graduate School of Medicine

Yamanashi
Japan

Schuichi Koizumi

University of Yamanashi - Interdisciplinary Graduate School of Medicine

Yamanashi
Japan

Masayuki Takeda

University of Yamanashi - Department of Urology ( email )

Yamanashi
Japan

Click here to go to TheLancet.com

Paper statistics

Abstract Views
142
Downloads
9