Inhibition of the cation channel TRPV4 improves bladder function in mice and rats with cyclophosphamide-induced cystitis
Inhibition of the cation channel TRPV4 improves bladder function in mice and rats with cyclophosphamide-induced cystitis
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DOI：
10.1073/pnas.1005333107
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发表时间：
2010-11-02
影响因子：
11.1
通讯作者：
Voets, Thomas
中科院分区：
文献类型：
--
作者：
Everaerts, Wouter;Zhen, Xiaoguang;Voets, Thomas
功能性膀胱容量降低和伴随的排尿频率增加（Plorakisuria）是与膀胱炎，前列腺增生，神经系统疾病和过度活跃膀胱综合征相关的常见尿路症状。这些症状可能会深刻影响受苦个体的生活质量，但可用的药理学治疗通常不令人满意。最近的工作表明，阳离子通道TRPV4在尿路上皮细胞中高度表达，并在感测正常的膀胱填充状态中起作用。在本文中，我们表明，在TRPV4（ - / - ）小鼠中，膀胱炎诱导的膀胱功能障碍的发育受到严重损害。此外，我们描述了HC-067047，这是一种先前未表征，有效和选择性的TRPV4拮抗剂，可增加功能性膀胱容量，并降低WT小鼠和大鼠患有膀胱炎的排尿频率。 HC-067047不影响TRPV4（ - / - ）小鼠中的膀胱功能，证明其体内效应对靶标。这些结果表明，TRPV4拮抗剂可以提供一种有希望的治疗膀胱功能障碍的方法。
Reduced functional bladder capacity and concomitant increased micturition frequency (pollakisuria) are common lower urinary tract symptoms associated with conditions such as cystitis, prostatic hyperplasia, neurological disease, and overactive bladder syndrome. These symptoms can profoundly affect the quality of life of afflicted individuals, but available pharmacological treatments are often unsatisfactory. Recent work has demonstrated that the cation channel TRPV4 is highly expressed in urothelial cells and plays a role in sensing the normal filling state of the bladder. In this article, we show that the development of cystitis-induced bladder dysfunction is strongly impaired in Trpv4(-/-) mice. Moreover, we describe HC-067047, a previously uncharacterized, potent, and selective TRPV4 antagonist that increases functional bladder capacity and reduces micturition frequency in WT mice and rats with cystitis. HC-067047 did not affect bladder function in Trpv4(-/-) mice, demonstrating that its in vivo effects are on target. These results indicate that TRPV4 antagonists may provide a promising means of treating bladder dysfunction.