Different effects of GsMTx4 on nocturia associated with the circadian clock and Piezo1 expression in mice
Different effects of GsMTx4 on nocturia associated with the circadian clock and Piezo1 expression in mice
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DOI：
10.1016/j.lfs.2021.119555
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发表时间：
2021-04-28
期刊：
影响因子：
6.1
通讯作者：
Takeda, Masayuki
中科院分区：
文献类型：
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作者：
Ihara, Tatsuya;Mitsui, Takahiko;Takeda, Masayuki
目的：夜尿症是老年患者的一个主要问题。时钟基因调节膀胱昼夜功能和感知膀胱充盈的压电型机械敏感离子通道成分1 （Piezo1）。我们利用WT和Clock突变（Clock(Delta 19/Delta 19)：夜尿症表型）小鼠来确定GsMTx4（一种Piezo1抑制剂）的作用是否依赖于膀胱中昼夜节律的Piezo1表达。方法：比较小鼠给药、低剂量、高剂量GsMTx4后的排尿行为。在授时时间（ZT） 0、Piezo1低表达期（ZT0-IP）和ZT12、Piezo1高表达期（ZT12-IP）进行腹腔注射（IP）。使用代谢笼测量尿量（Uvol）、排尿频率（VF）和每空尿量（Uvol/v）。结果：高剂量GsMTx4可降低WT小鼠ZT12-IP的VF，而对Clock（Delta 19/Delta 19）小鼠无影响。两种剂量后，WT小鼠的VF在ZT0-IP时均显著降低，而Clock（Delta 19/Delta 19）小鼠的VF仅在高剂量后降低。两种剂量的ZT0-IP和高剂量的ZT12-IP均使WT小鼠的Uvol/v增加。高剂量后，仅在ZT0-IP时，Clock（Delta 19/Delta 19）小鼠的Uvol/v升高。GsMTx4不影响ZT12-IP小鼠的Uvol。两种小鼠在ZT0-IP时均观察到Uvol下降；但与GsMTx4-IP无关。结论：GsMTx4的作用与生物钟和Piezo1表达水平有关。夜尿症在睡眠阶段的效果最大。这些结果可能导致夜尿症的新治疗策略。
Objectives: Nocturia is a major problem in geriatric patients. Clock genes regulate circadian bladder function and Piezo type mechanosensitive ion channel component 1 (Piezo1) that senses bladder fullness. We utilized WT and Clock mutant (Clock(Delta 19/Delta 19): nocturia phenotype) mice to determine if the effects of GsMTx4, a Piezo1 inhibitor, is dependent on circadian Piezo1 expression in the bladder.Methods: We compared voiding behavior in mice after the administration of vehicle, low dose, or high dose of GsMTx4. Intraperitoneal injections (IP) were performed at Zeitgeber time (ZT) 0, lower Piezo1 expression phase (ZT0-IP) and ZT12, higher Piezo1 expression phase (ZT12-IP). Urine volume (Uvol), voiding frequency (VF), and urine volume per void (Uvol/v) were measured using metabolic cages.Results: VF decreased at ZT12-IP in WT mice only with high dose of GsMTx4 but showed no effects in Clock(Delta 19/Delta 19) mice. VF decreased significantly at ZT0-IP in WT mice after both doses, but only decreased after high dose in Clock(Delta 19/Delta 19) mice. Uvol/v increased in WT mice at ZT0-IP after both doses and at ZT12-IP after high dose. Uvol/v increased in Clock(Delta 19/Delta 19) mice only at ZT0-IP after high dose. GsMTx4 did not affect Uvol in both mice at ZT12-IP. A decrease in Uvol was observed in both mice at ZT0-IP; however, it was unrelated to GsMTx4-IP.Conclusions: The effects of GsMTx4 changed associated with the circadian clock and Piezo1 expression level. The maximum effect occurred during sleep phase in WT. These results may lead to new therapeutic strategies against nocturia.