Presence of multiple peripheral circadian oscillators in the tissues controlling voiding function in mice

Jong-Yun Noh,Sung-Eun Kim,Kyungjin Kim,Sehyung Cho,Chang-Ju Kim,Mi-Hee Kim,Han Kyoung Choe,Dong-Hee Han,Il-Gyu Ko,Khae-Hawn Kim,Noheon Park

doi:10.1038/emm.2013.153

Abstract

Circadian clocks are the endogenous oscillators that harmonize a variety of physiological processes within the body. Although many urinary functions exhibit clear daily or circadian variation in diurnal humans and nocturnal rodents, the precise mechanisms of these variations are as yet unclear. In the present study, we demonstrate that Per2 promoter activity clearly oscillates in neonate and adult bladders cultured ex vivo from Per2::Luc knock-in mice. In subsequent experiments, we show that multiple local oscillators are operating in all the bladder tissues (detrusor, sphincter and urothelim) and the lumbar spinal cord (L4–5) but not in the pontine micturition center or the ventrolateral periaqueductal gray of the brain. Accordingly, the water intake and urine volume exhibited daily and circadian variations in young adult wild-type mice but not in Per1−/−Per2−/− mice, suggesting a functional clock-dependent nature of the micturition rhythm. Particularly in PDK mice, the water intake and urinary excretion displayed an arrhythmic pattern under constant darkness, and the amount of water consumed and excreted significantly increased compared with those of WT mice. These results suggest that local circadian clocks reside in three types of bladder tissue and the lumbar spinal cord and may have important roles in the circadian control of micturition function.

Highlights

Organisms on this rotating planet have adaptations for periodic changes in environmental conditions, such as environmental illumination, temperature, humidity, and food and predator availability
The persistent oscillation of circadian clock genes in separated bladder tissues indicates the intrinsic nature of local peripheral clocks in the three functional tissues of the bladder
We demonstrated that local circadian clockworks operate intrinsically in the bladder and lumbar spinal cord, the local regions that control voiding function in mice, even in the absence of extrinsic time cues

Summary

Introduction

Organisms on this rotating planet have adaptations for periodic changes in environmental conditions, such as environmental illumination, temperature, humidity, and food and predator availability. Distinct daily variations in urinary function and behavior are obvious in diurnal humans and nocturnal rodents.[6,7,8] Intuitively, most urine production and voiding should occur during the active phase, whereas better rest and sleep require increased storage of urine in the bladder and reduced urination frequency. Nocturia, abnormal waking during the night one or more times to void,[9,10,11] is known to decrease quality of life and negatively affects morbidity and mortality, especially in the elderly.[12,13,14,15] Possible causes of nocturia have been attributed to bladder storage problems, diurnal polyuria and nocturnal polyuria,[10] but the presence and functionality of local peripheral clocks in the regions controlling voiding functions have not yet been fully established. The possible existence of local peripheral clocks in the tissues controlling micturition function has yet to be determined

Methods

Results

Conclusion