Accumulating evidence suggests the etiology of nocturia may be attributed to disruptions in the rhythms of sleep-wake cycles, urine production, and bladder capacity (we refer to it as the brain–kidney–bladder circadian axis). Therefore, this review is composed from a chronobiological perspective to discuss the molecular mechanisms of the circadian clock regulatory cycle and discuss how desynchronized circadian rhythms of the brain, kidney, and bladder can contribute to nocturia.
The daily rhythm of human behaviour and physiology is regulated by the transcription-translation feedback loop, which exists both in the brain and in peripheral metabolic tissues, consisting of oppositional transcriptional activators (CLOCK and BMAL1) and repressors (PER and CRY). The hierarchical organization of the circadian system, from the master pacemaker to extra-SCN clocks, regulates multiple physiological functions; whereas, dysregulated circadian mechanisms participate in several pathophysiological dysfunctions, such as nocturia.
At the brain level, the arousal threshold is high during the main sleep period to avoid external and internal disturbance, partially owing to the circadian secretion of melatonin. Vasopressin is periodically secreted from the posterior pituitary gland to promote the reabsorption of water in the collecting duct of the nephron. Under pathophysiological states, disruption of the central clock in the suprachiasmatic nucleus and neuroendocrine system leads to nocturia through impaired sleep quality and misaligned release of hormones such as melatonin and arginine vasopressin.
To reduce nocturnal urine volume, the kidney sets its own circadian pattern with a reduced glomerular filtration rate and increased water reabsorption during sleep, in response to the rhythmic fluctuation of blood pressure, electrolytes, and hormones. These chronobiological phenomena are guarded by the peripheral clock genes. For example, in proximal tubule cells, Period 1 (PER1) positively regulates the expression of SLC5A1 and SLC9A3, the encoding genes of the sodium-glucose co-transporter 1 and Na+/H+ exchanger 3, respectively. Therefore, it is not surprising that disturbance of the renal circadian mechanism is increasingly recognized as a risk factor for nocturia, suggestive of nocturnal polyuria.
Furthermore, the circadian expression of peripheral clock genes in the bladder leads to time-dependent variations of bladder sensation and excitability. For instance, in the urothelium, there are several rhythmic expressed mechanosensitive receptors, such as PIEZO1 and transient receptor potential cation channel subfamily V member 4, which contribute to the circadian control of ATP release, mediating the bladder’s sensory response to distension through activation of P2 receptors. In pathophysiological states, the disorganized circadian expression of these mechanosensors contributes to nocturia onset.
Expanding knowledge of the molecular basis of circadian regulation and dysregulation within the brain-kidney-bladder circadian axis will help develop strategies for the prevention, management, and treatment of nocturia based on chronobiology. The potential chronotherapies could base on environmental and behavioural changes, such as timed feeding, timed fluid consumption, timed light exposure, and timed physical activity. Direct manipulation of the transcription-translation feedback loop using small-molecule modulators is also an intriguing approach to regulating circadian oscillators, including clock modulators (KL001, SHP656, KL101, TH301 and KS15), REV-ERB agonists (SR0990 and SR9011) and the ROR agonist (nobiletin). However, future studies are needed to determine the feasibility of circadian behaviour therapy as well as the safety and efficacy of clock gene modulators for patients with nocturia.
Written by:
- Qi-Xiang Song, MD, PhD, Associate Professor, Department of Urology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Pudong District, Shanghai, China
- Margot Damaser, PhD, Department of Biomedical Engineering, Lerner Research Institute and Glickman Urological and Kidney Institute, Cleveland Clinic, Advanced Platform Technology Center, Louis Stokes Cleveland VA Medical Center, Cleveland, OH