(1) Department Of Urology, University Of Yamanashi, , Japan, (2) Department Of Immunology, University Of Yamanashi, , Japan
Circadian gene expression, generated by clock genes, regulates many aspects of behavior and physiological processes, and abnormalities in clock genes have been reported to be associated with various diseases. Lower urinary tract functions are also associated with the circadian rhythm and clock gene regulation, and nocturia are exacerbated with the dysregulation of clock genes (1). Intermittent stress disrupts the circadian rhythm only in peripheral organs (2). Here, the effect of restraint stress (RS) on circadian bladder function was investigated based on urination behavior and gene expression rhythms. PF670462 (PF), Per2 phosphorylation enzyme inhibitor, was administered to investigate the effects of circadian bladder re-alignment after RS.
Two hours RS during the light phase (from ZT4 to ZT6) was applied to mice (RS mice) for 5 days. 10mg/kg PF was administered intraorally for 5 days at the same time of RS (RS+PF mice). The following parameters were then measured: urination behaviors using metabolic cages; in vivo Per2 expression rhythms in the bladder of Period2 luciferase knock-in mice using in vivo imaging system.
In the measurement of urination behavior, control mice did not show altered urination behavior in the light phase however, RS mice exhibited a higher voiding frequency and lower bladder capacity. In in vivo imaging, the rhythmic expression of Per2 observed in control mice was also altered in RS mice (Fig.1A and B). After PF administration, voiding frequency was reduced and bladder capacity was increased during the light phase in RS+PF mice; the in vivo Per2 expression rhythm was also fully restored (Fig.1C).
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.