Deletion of the transient receptor potential cation channel TRPV4 impairs murine bladder voiding
Thomas Gevaert, … , Dirk De Ridder, Bernd Nilius
Thomas Gevaert, … , Dirk De Ridder, Bernd Nilius
Published October 18, 2007
Citation Information: J Clin Invest. 2007;117(11):3453-3462. https://doi.org/10.1172/JCI31766.
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Deletion of the transient receptor potential cation channel TRPV4 impairs murine bladder voiding

Abstract

Here we provide evidence for a critical role of the transient receptor potential cation channel, subfamily V, member 4 (TRPV4) in normal bladder function. Immunofluorescence demonstrated TRPV4 expression in mouse and rat urothelium and vascular endothelium, but not in other cell types of the bladder. Intracellular Ca2+ measurements on urothelial cells isolated from mice revealed a TRPV4-dependent response to the selective TRPV4 agonist 4α-phorbol 12,13-didecanoate and to hypotonic cell swelling. Behavioral studies demonstrated that TRPV4–/– mice manifest an incontinent phenotype but show normal exploratory activity and anxiety-related behavior. Cystometric experiments revealed that TRPV4–/– mice exhibit a lower frequency of voiding contractions as well as a higher frequency of nonvoiding contractions. Additionally, the amplitude of the spontaneous contractions in explanted bladder strips from TRPV4–/– mice was significantly reduced. Finally, a decreased intravesical stretch-evoked ATP release was found in isolated whole bladders from TRPV4–/– mice. These data demonstrate a previously unrecognized role for TRPV4 in voiding behavior, raising the possibility that TRPV4 plays a critical role in urothelium-mediated transduction of intravesical mechanical pressure.

Authors

Thomas Gevaert, Joris Vriens, Andrei Segal, Wouter Everaerts, Tania Roskams, Karel Talavera, Grzegorz Owsianik, Wolfgang Liedtke, Dirk Daelemans, Ilse Dewachter, Fred Van Leuven, Thomas Voets, Dirk De Ridder, Bernd Nilius

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Figure 1

Immunohistochemical and functional evidence for TRPV4 on urothelium.

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Immunohistochemical and functional evidence for TRPV4 on urothelium. (A–...
(A–D) Confocal laser scanning microphotographs of mouse bladder with staining against TRPV4 in mouse bladder. Scale bars: 50 μm (A and B), 250 μm (C and D). (A) Urothelium from TRPV4+/+ mouse is immunoreactive for TRPV4 (white arrows). TRPV4 immunoreactivity delineates multiple layers of urothelial cells. Notice nonspecific, non-TRPV4 immunoreactivity in the suburothelium (red arrow). (B) Urothelium from TRPV4–/– mouse is not immunoreactive for TRPV4 (white arrows). Suburothelial nonspecific, non-TRPV4 immunoreactivity is indicated by the red arrow. (C) Full thickness slide of TRPV4+/+ bladder, delineated by luminal (L) and serosal (S) borders. Notice urothelial TRPV4 immunoreactivity (white arrows), suburothelial non-TRPV4 immunoreactivity (full red arrow), and detrusor nonspecific fluorescence (broken red arrow). (D) Full thickness slide of TRPV4–/– bladder delineated by luminal and serosal borders. Notice absence of urothelial TRPV4 immunoreactivity (white arrows), presence of suburothelial non-TRPV4 immunoreactivity (full red arrow), and detrusor nonspecific fluorescence (broken red arrow). (E) Time course of [Ca2+]i increase caused by application of 5 μM 4α-PDD. Black lines indicate TRPV4+/+; n = 20). Gray lines indicate TRPV4–/– mice (n = 20). Solid lines indicate mean, and dotted lines indicate SEM. (F) Average [Ca2+]i increases in urothelium isolated from TRPV4+/+ (black bars) and TRPV4–/– (white bars) mice in response to application of 5 μM 4α-PDD, hypotonic solution, and 100 nM ATP. All data represent mean ± SEM, by unpaired Student’s t test. *P < 0.05.