Augmented bladder urothelial polyamine signaling and block of BK channel in the pathophysiology of overactive bladder syndrome.
Augmented bladder urothelial polyamine signaling and block of BK channel in the pathophysiology of overactive bladder syndrome.
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DOI：
10.1152/ajpcell.00259.2009
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发表时间：
2009-12
期刊：
影响因子：
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通讯作者：
Mingkai Li;Yan Sun;J. Simard;Jian-Ying Wang;T. Chai
中科院分区：
文献类型：
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作者：
Mingkai Li;Yan Sun;J. Simard;Jian-Ying Wang;T. Chai
膀胱过度活动综合征（OAB）是一种以尿急和急迫性尿失禁为特征的特发性疾病。逼尿肌过度活动传统上被描述为OAB的生理机制。然而，膀胱尿路梗阻（BU）也可能参与其病理生理过程。本研究测量了无症状和OAB受试者的膀胱尿路上皮细胞（布克）中多胺信号及其对膜电导率的下游效应。用免疫组织荧光法检测BU中鸟氨酸脱羧酶（ODC）的表达。从BU活检中培养的布克用于电生理学研究。dl-α-二氟甲基鸟氨酸（DFMO）、精胺或亚精胺用于调节布克中的多胺信号传导。结果显示ODC在OAB BU中过表达。在OAB布克中，全细胞和细胞附着构型显示出显著降低的电流。使用由内而外的补丁，外向电流显着增加，表明在OAB布克的外向电流块的细胞质来源。在对照布克，外向电流介导的大电导钙激活钾（BK）通道由于钙剂量依赖性和阻断伊比利亚毒素。亚精胺和精胺以剂量依赖方式阻断正常布克细胞的外向电流。DFMO可显著增加OAB布克C的外向电流（P < 0.01）。加入精胺和亚精胺后，DFMO处理的OAB布克细胞的外向电流显著降低（P < 0.05）。这些数据表明，多胺信号在OAB尿激酶和OAB布克中上调。此外，布克中的多胺阻断BK通道。靶向膀胱尿路上皮多胺信号转导可能代表了基于病理生理机制的OAB治疗的新方法。
Overactive bladder syndrome (OAB) is an idiopathic condition characterized by urinary urgency and urge incontinence. Detrusor overactivity has been traditionally described as the physiologic mechanism for OAB. However, the bladder urothelium (BU) may also be involved in the pathophysiology. This study measured polyamine signaling and its downstream effects on membrane conductivity in bladder urothelial cells (BUC) obtained from asymptomatic and OAB subjects. Immunohistofluorescence was used to measure ornithine decarboxylase (ODC) expression in BU. BUC, cultured from BU biopsies, were used for electrophysiologic studies. dl-alpha-Difluoromethylornithine (DFMO), spermine, or spermidine was used to modulate polyamine signaling in BUC. Results showed ODC overexpression in OAB BU. In OAB BUC, whole cell and cell-attached configuration showed significantly decreased currents. Using inside-out patches, outward currents increased significantly, suggesting a cytoplasmic source of the outward current block in OAB BUC. In control BUC, outward currents were mediated by the large-conductance calcium-activated potassium (BK) channel due to calcium dose-dependence and block by iberiotoxin. Spermidine and spermine blocked the outward current in normal BUC in dose-dependent fashion. Conversely, DFMO significantly increased (P < 0.01) outward currents in OAB BUC both in cell-attached and in whole cell configuration. The outward currents in DFMO-treated-OAB BUC could be significantly reduced (P < 0.05) by adding back spermidine and spermine. These data suggest that polyamine signaling is upregulated in OAB urothelium and OAB BUC. Furthermore, polyamines in BUC block the BK channel. Targeting of bladder urothelial polyamine signaling may represent a novel approach for OAB treatment based on pathophysiologic mechanisms.