Intermittent restraint stress induces circadian misalignment in the mouse bladder, leading to nocturia

Abstract

Intermittent stress disrupts the circadian rhythm in clock genes such as Per2 only in peripheral organs without any effect on the central circadian clock in the suprachiasmatic nucleus. 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. Two-hour RS during the light (sleep) 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 such as piezo type mechanosensitive ion channel component 1 ( Piezo1 ), transient receptor potential cation channel subfamily V member 4 ( TRPV4 ), and Connexin26 ( Cx26 ) in the bladder mucosa; Per2 expression in the excised bladder of Per2 luciferase knock-in mice (Per2::luc); in vivo Per2 expression rhythms in the bladder of Per2::luc mice. 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 Piezo1 , TRPV4 , Connexin26 , 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. Therefore, 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.

Persistent myopathy despite release of partial obstruction: in vivo reversal of dysfunction and transcriptional responses using rapamycin

“…Our findings are also corroborated by data in human studies. The expression of key clock genes and their proteins found in rodent bladders is also shown in human bladder tissues . Furthermore, circadian dysregulation may also cause bladder pathologies in humans including bladder cancer, prostate cancer, LUTS, nocturia, and overactive bladder .…”

Psychological/mental stress‐induced effects on urinary function: Possible brain molecules related to psychological/mental stress‐induced effects on urinary function

“…In mice exposed to restraint stress (2 h daily for 5 consecutive days), a well-known psychiatric stressor in rodents, 67 higher voiding frequency and lower BC were observed compared with control mice. 68 Conversely, in other reports, restraint stress exposure for 30 min daily for 7 consecutive days in rats or for 4 h daily for 21 consecutive days in mice showed no obvious effect on urinary function. 2,46 Therefore, the effects of restraint stress exposure on urinary function seem to be different depending on the frequency, duration and intensity of restraint.…”

Emerging roles of the TRPV4 channel in bladder physiology and dysfunction

“…Disruption of this normal bladder circadian rhythm due to the abnormality of the clock gene may underlie nocturia associated with unwanted hyperactivity of the bladder when sleeping. There has been evidence that expression of TRPV4 and other elements of urothelial sensory transduction exhibit a circadian rhythm (Ihara et al 2017(Ihara et al , 2019. This means that clock genes can regulate sensory transduction in the bladder and TRPV4-mediated ATP release might trigger nocturia.…”

“…There has been evidence that expression of TRPV4 and other elements of urothelial sensory transduction exhibit a circadian rhythm (Ihara et al . 2017, 2019). This means that clock genes can regulate sensory transduction in the bladder and TRPV4‐mediated ATP release might trigger nocturia.…”