Inhibition of the cation channel TRPV4 improves bladder function in mice and rats with cyclophosphamide-induced cystitis

被引：344

作者：

Everaerts, Wouter ^{[2
,3
,4
]}

Zhen, Xiaoguang ^{[1
]}

Ghosh, Debapriya ^{[2
,4
]}

Vriens, Joris ^{[2
,4
]}

Gevaert, Thomas ^{[3
,5
]}

Gilbert, James P. ^{[1
]}

Hayward, Neil J. ^{[1
]}

McNamara, Colleen R. ^{[1
]}

Xue, Fenqin ^{[2
,4
]}

Moran, Magdalene M. ^{[1
]}

Strassmaier, Timothy ^{[1
]}

Uykal, Eda ^{[1
]}

Owsianik, Grzegorz ^{[2
,4
]}

Vennekens, Rudi ^{[2
,4
]}

De Ridder, Dirk ^{[3
,4
]}

Nilius, Bernd ^{[2
,4
]}

Fanger, Christopher M. ^{[1
]}

Voets, Thomas ^{[2
,4
]}

机构：

[1] Hydra Biosci, Cambridge, MA 02139 USA

[2] Katholieke Univ Leuven, Dept Mol Cell Biol, Lab Ion Channel Res, B-3000 Louvain, Belgium

[3] Katholieke Univ Leuven, Dept Surg, Lab Expt Urol, B-3000 Louvain, Belgium

[4] Katholieke Univ Leuven, TRP Res Platform Leuven TRPLe, B-3000 Louvain, Belgium

[5] Katholieke Univ Leuven Hosp, Dept Morphol & Mol Pathol, B-3000 Louvain, Belgium

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2010年 / 107卷 / 44期

关键词：

transient receptor potential channels; urothelium; RECEPTOR POTENTIAL VANILLOID-4; OVERACTIVE BLADDER; URINARY-BLADDER; NEUROGENIC INFLAMMATION; LACKING TRPV4; TRANSIENT; ACTIVATION; CONTRACTION; ANTAGONIST; MUTATIONS;

D O I：

10.1073/pnas.1005333107

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

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.

引用

页码：19084 / 19089

页数：6

共 41 条

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