Abstract
Circadian expression rhythms of clock gene products in the bladder are reportedly hindered by clock gene abnormalities. However, the role of clock gene products in various pathological lower urinary tract conditions is unknown. The present study examined the relationship between clock genes and voiding dysfunction in spontaneous hypertensive rats (SHR). The voluntary voiding behavior study using metabolic cages was performed in 18-weeks old male Wistar rats (control group, n = 36) and SHR (SHR group, n = 36) under 12-h light/12-h dark conditions. Bladders were harvested every 4 h at six time points (n = 6 for each time point for each group), and we analyzed the messenger RNA (mRNA) expression of several clock genes: period 2 (Per2), cryptochrome 2 (Cry2), brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein 1 (Bmal1), circadian locomotor output cycles kaput (Clock), nuclear receptor subfamily 1, group D, member 1 (Rev-erbα), mechanosensors: transient receptor potential vanilloid channel 1 (TRPV1), TRPV4, Piezo1, and vesicular nucleotide transporter (VNUT) using real-time polymerase chain reaction. Though 24-h urination frequency for both light and dark periods was significantly higher in the SHR group, urine volume per voiding was significantly lower versus control. In controls, urine volume per voiding was significantly lower during the dark period (active phase) than the light period (rest phase); this parameter did not significantly differ between active and rest phases for SHR. SHR bladders showed significantly higher expression of Cry2 and Clock during the active phase compared to controls. In the SHR group, TRPV1, TRPV4, Piezo1, and VNUT mRNA levels were significantly higher during the active phase compared to the control group. We speculate that Cry2 and Clock may be contributing factors in the decrease of bladder capacity during the active phase in SHR through increase of TRPV1, TRPV4, Piezo1, and VNUT expression, but further research will be necessary to elucidate the precise mechanisms.
Highlights
Circadian rhythms are under the control of clock gene products, which are present in most cells and organs of mammals
Body and bladder weights were significantly lower in the spontaneously hypertensive rats (SHR) group than in the control (Fig 1A and 1B), while 24-h voiding frequency in both the rest and active phases was significantly higher in the SHR group (Fig 1C)
The voided volume in the active phase was significantly higher than that in the rest phase for both groups, the 24-h urine volume in the active phase was significantly lower in the SHR group compared to the control group (Fig 1D)
Summary
Circadian rhythms are under the control of clock gene products, which are present in most cells and organs of mammals. The suprachiasmatic nucleus of the brain works as a master pacemaker [1] and synchronizes peripheral clock gene rhythms that exist in multiple tissues of the whole body, such as the lungs, liver, kidneys, and bladder [2, 3]. The mechanisms of these synchronizing pathways are likely to involve both hormonal and neuronal mechanisms; other pathways are not completely understood. Several groups have reported that lower urinary tract functions are regulated by clock genes [6, 7]
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