Beča Katharine I K, Girard Beatrice M, Heppner Thomas J, Hennig Grant W, Herrera Gerald M, Nelson Mark T, Vizzard Margaret A
Department of Neurological Sciences, The Larner College of Medicine, University of Vermont, Burlington, VT, United States.
Department of Pharmacology, The Larner College of Medicine, University of Vermont, Burlington, VT, United States.
Front Pain Res (Lausanne). 2021 Oct 12;2:748385. doi: 10.3389/fpain.2021.748385. eCollection 2021.
In the urinary bladder, mechanosensitive ion channels (MSCs) underlie the transduction of bladder stretch into sensory signals that are relayed to the PNS and CNS. PIEZO1 is a recently identified MSC that is Ca permeable and is widely expressed throughout the lower urinary tract. Recent research indicates that PIEZO1 is activated by mechanical stretch or by pharmacological agonism via Yoda1. Aberrant activation of PIEZO1 has been suggested to play a role in clinical bladder pathologies like partial bladder outlet obstruction and interstitial cystitis/bladder pain syndrome (IC/BPS). In the present study, we show that intravesical instillation of Yoda1 in female Wistar rats leads to increased voiding frequency for up to 16 hours after administration compared to vehicle treatment. In a cyclophosphamide (CYP) model of cystitis, we found that the gene expression of several candidate MSCs (, and ) were all upregulated in the urothelium and detrusor following chronic CYP-induced cystitis, but not acute CYP-induced cystitis. Functionally with this model, we show that Ca activity is increased in urothelial cells following PIEZO1 activation via Yoda1 in acute and intermediate CYP treatment, but not in naïve (no CYP) nor chronic CYP treatment. Lastly, we show that activation of PIEZO1 may contribute to pathological bladder dysfunction through the downregulation of several tight junction genes in the urothelium including claudin-1, claudin-8, and zona occludens-1. Together, these data suggest that PIEZO1 activation plays a role in dysfunctional voiding behavior and may be a future, clinical target for the treatment of pathologies like IC/BPS.
在膀胱中，机械敏感离子通道（MSCs）是膀胱牵张转化为感觉信号的基础，这些信号会传递至外周神经系统（PNS）和中枢神经系统（CNS）。PIEZO1是最近发现的一种机械敏感离子通道，具有钙离子通透性，在整个下尿路广泛表达。近期研究表明，PIEZO1可被机械牵张或通过Yoda1的药理学激动作用激活。PIEZO1的异常激活被认为在诸如膀胱出口部分梗阻和间质性膀胱炎/膀胱疼痛综合征（IC/BPS）等临床膀胱疾病中起作用。在本研究中，我们发现，与赋形剂处理相比，向雌性Wistar大鼠膀胱内灌注Yoda1后，给药后长达16小时排尿频率增加。在膀胱炎的环磷酰胺（CYP）模型中，我们发现，在慢性CYP诱导的膀胱炎后，尿路上皮和逼尿肌中几种候选机械敏感离子通道（ 、 和 ）的基因表达均上调，但急性CYP诱导的膀胱炎后未上调。在该模型的功能研究中，我们发现，在急性和中期CYP处理中，通过Yoda1激活PIEZO1后，尿路上皮细胞中的钙离子活性增加，但在未处理（无CYP）或慢性CYP处理中未增加。最后，我们发现，PIEZO1的激活可能通过下调尿路上皮中包括闭合蛋白-1、闭合蛋白-8和紧密连接蛋白-1在内的几种紧密连接基因，导致病理性膀胱功能障碍。总之，这些数据表明，PIEZO1的激活在排尿功能障碍行为中起作用，可能是未来治疗IC/BPS等疾病的临床靶点。
