Disruption of circadian rhythm as a potential pathogenesis of nocturia

Abstract

Increasing evidence suggested the multifactorial nature of nocturia, but the true pathogenesis of this condition still remains to be elucidated. Contemporary clinical medications are mostly symptom based, aimed at either reducing nocturnal urine volume or targeting autonomic receptors within the bladder to facilitate urine storage. The day-night switch of the micturition pattern is controlled by circadian clocks located both in the central nervous system and in the peripheral organs. Arousal threshold and secretion of melatonin and vasopressin increase at night-time to achieve high-quality sleep and minimize nocturnal urine production. In response to the increased vasopressin, the kidney reduces the glomerular filtration rate and facilitates the reabsorption of water. Synchronously, in the bladder, circadian oscillation of crucial molecules occurs to reduce afferent sensory input and maintain sufficient bladder capacity during the night sleep period. Thus, nocturia might occur as a result of desynchronization in one or more of these circadian regulatory mechanisms. Disrupted rhythmicity of the central nervous system, kidney and bladder (known as the brain-kidney-bladder circadian axis) contributes to the pathogenesis of nocturia. Novel insights into the chronobiological nature of nocturia will be crucial to promote a revolutionary shift towards effective therapeutics targeting the realignment of the circadian rhythm.

Figure 1.. Transcription-translation feedback loop and the brain-kidney-bladder circadian axis.

The central circadian pacemaker, located in the suprachiasmatic nucleus (SCN), is regulated by the transcription-translation feedback loop (TTFL), which mainly consists of a primary and a secondary loop (A). In the primary loop, circadian locomotor output cycles kaput (CLOCK) and brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein 1 (BMAL1) heterodimers bind to the E box of the promoters of the target genes period (PER) and cryptochrome (CRY) and induce their transcription. In a negative feedback fashion, the excessive production of PER and CRY proteins inhibits the transcriptional activity of CLOCK–BMAL1 and leads to the self-degradation of PER and CRY . Once the level of PER and CRY drop to sufficient levels, CLOCK— BMAL1-mediated transcription can be restarted. In the secondary loop, the CLOCK— BMAL1 complex also induces the expression of the nuclear receptors REV-ERB, retinoid-related orphan receptor (ROR), and D-box binding protein (DBP). REV-ERB and ROR repress and activate the transcription of BMAL1, respectively, through binding to the ROR/REV-ERB-response element (RORE). DBP activates D-box-dependent transcription, leading to the expression of ROR. This process can be inhibited by NFIL3, a transcriptional repressor that binds to D-box genes. NFIL3 transcription can be activated or repressed by the binding of REV-ERB and ROR to RORE, respectively. The TTFL also exists in multiple peripheral organs besides SCN. Nocturia has been shown to have a chronobiological nature involving a set of autonomous but integrated circadian rhythmic mechanisms in the brain, kidney and bladder, known as the brain-kidney-bladder circadian axis (B). In people without nocturia or LUTS during sleep (Ba) , the brain sets up a high arousal threshold during the main sleep period to avoid external and internal disturbance. Vasopressin is periodically secreted from the posterior pituitary gland to promote the reabsorption of water in the collecting duct of the nephron. To further reduce urine production, the kidney has its own circadian pattern with reduced glomerular filtration rate (GFR) during sleep. Bladder function also changes in a circadian fashion, with increased storage capacity and decreased sensory afferent transmission during main sleeping hours to minimize the voiding episodes. Nocturia (Bb) might arise from disruption in one or more of these circadian regulation patterns in the brain-kidney-bladder axis, which leads to sleep disorders, increased nocturnal urine production and reduced nocturnal bladder capacity.

Figure 2.. PER1-mediated circadian control of the nephron.

Period 1 (PER1) was shown to be involved in the transcriptional regulation of genes encoding crucial proteins modulating solute reabsorption along the nephron. In proximal tubule cells, PER1 positively regulates the expression of SLC5a1 and SLC9a3 (encoding the sodium-glucose co-transporter 1 (SGLT1) and Na⁺/H⁺ exchanger 3 (NHE3), respectively). In distal tubule cells, PER1 regulates the expression levels of SLC12a3 (encoding the Na-Cl co-transporter (NCC)), and of genes encoding components of the with-no-lysine kinase (WNK) pathway, such as WNK1, WNK4 and KS-WNK1 (a kidney-specific WNK1 isoform), which regulate NCC activity. In collecting duct cells, PER1 regulates the expression of the Na, K-ATPase positive regulator FXDY5, in turn modulating this Na, K-ATPase activity. Additionally, PER1 regulates the activity of the epithelial sodium channel (ENaC), both by regulating the expression of SCNN1, which encodes the α-ENaC subunit, and of UBE2e3 and caveolin-1 (CAV1), which are negatively regulators of ENaC. PER1 also negatively regulates the expression of END1, encoding Endothelin-1, which is a negative regulator of ENaC. In the collecting duct cells, PER1 is also positively regulated by aldosterone and mediates the downstream effects of aldosterone on ENaC .

Figure 3.. Putative role of the urothelium in the physiological diurnal rhythm of bladder capacity (modified from ref 196).

The circadian modulation of bladder function by the peripheral bladder clock is shown. The diurnal rhythm of molecular mediators, including CX43, CX26, VNUT, and mechanosensors such as Piezo1 and TRPV4, regulates ATP release in response to bladder distension, influencing urinary sensation and bladder capacity. During the active (dark) phase, the expression of CX43, CX26 and VNUT peaks, facilitating increased ATP release through the haemichannels formed by CX43 and CX26. This process leads to increased bladder sensitivity and modulation of bladder capacity. The mechanosensors Piezo1 and TRPV4 also show diurnal fluctuations, contributing to the circadian control of ATP release. Released ATP activates P2 receptors on afferent nerves, mediating the bladder’s sensory response to distension. In the resting (light) phase, the expression of these mediators decreases, resulting in reduced ATP release and reduced bladder excitability, supporting time-dependent regulation of bladder function in alignment with the circadian cycle. Abbreviations: Cx:26, connexin 26; Cx43, connexin 43; TRPV4, transient receptor potential cation channel subfamily V member 4; VNUT, vesicular nucleotide transporter; P2Rs, purinergic type 2 receptors.