The circadian rhythm of bladder clock genes in the spontaneously hypersensitive rat
The circadian rhythm of bladder clock genes in the spontaneously hypersensitive rat
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DOI：
10.1371/journal.pone.0220381
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发表时间：
2019-07-25
期刊：
影响因子：
3.7
通讯作者：
Takenaka, Atsushi
中科院分区：
文献类型：
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作者：
Kimura, Yusuke;Honda, Masashi;Takenaka, Atsushi
据报道，生物钟基因产物在膀胱中的昼夜表达节律受到生物钟基因异常的阻碍。然而，时钟基因产物在各种病理性下尿路疾病中的作用尚不清楚。本研究探讨了自发性高血压大鼠（SHR）生物钟基因与排尿功能障碍的关系。采用代谢笼法研究18周龄雄性Wistar大鼠（对照组，n = 36）和SHR （SHR组，n = 36）在12 h光照/12 h黑暗条件下的自愿排尿行为。在6个时间点每4小时采集膀胱（每组每个时间点n = 6），我们分析了几个时钟基因的信使RNA （mRNA）表达：周期2 （Per2）、隐色素2 （Cry2）、脑和肌肉香烃受体核易位样蛋白1 （Bmal1）、昼夜运动输出周期kaput （clock）、核受体亚家族1、D组、成员1 （Rev-erba）、机械传感器。瞬时受体电位香草蛋白通道1 （TRPV1）、TRPV4、Piezo1和囊泡核苷酸转运蛋白（VNUT）的实时聚合酶链反应。尽管SHR组在光照期和黑暗期的24小时排尿频率明显较高，但每次排尿量明显低于对照组。在对照组中，每次排尿量在黑暗期（活动期）明显低于光明期（休息期）；该参数在SHR的活动期和休止期之间无显著差异。与对照组相比，SHR膀胱在活动期Cry2和Clock的表达明显增加。在SHR组，TRPV1、TRPV4、Piezo1和VNUT mRNA水平在活动期明显高于对照组。我们推测Cry2和Clock可能通过增加TRPV1、TRPV4、Piezo1和VNUT的表达而导致SHR活动期膀胱容量下降，但需要进一步的研究来阐明其确切的机制。
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-erba), 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.