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 Ca 2+ 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 anxietyrelated 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.

TRPV4 channel participates in receptor-operated calcium entry and ciliary beat frequency regulation in mouse airway epithelial cells

“…1B were TRPV4 nonspecific. Similar nonspecific immunoreactivity has been reported in kidney sections of TRPV4 ϩ/ϩ and TRPV4 Ϫ/Ϫ mice probed with an antibody raised against the same C-terminal epitope of rat TRPV4 (29).…”

“…The facts that 4␣PDD binds and activates TRPV4 (17) without the involvement of PKC (16) and that the response to 4␣PDD is totally lost in different TRPV4 Ϫ/Ϫ cells (ref. 29 and this study) strongly suggest that the 4␣PDD effects are mainly TRPV4-mediated, although we cannot completely rule out the participation of other pathways.…”

“…The reduced Ca 2ϩ influx in TRPV4 Ϫ/Ϫ is also accompanied by a diminished response of the CBF to micromolar concentrations of ATP, confirming again the coupling of TRPV4 to CBF regulation. Interestingly, the lack of TRPV4 does not affect the Ca 2ϩ signal [as reported for TRPV4 Ϫ/Ϫ urothelial cells (29)] or CBF acceleration induced by 200 nM ATP. At this low ATP concentration, the Ca 2ϩ signal in tracheal cells is mainly oscillatory, a pattern that, at least for HEK cells, has been associated with the activity of store-operated pathways involving STIM1 and ORAI1 proteins without major contribution of TRP channels (43).…”

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

“…In naive WT mice, we measured a regular pattern of pressure build-up and voiding ( Fig. 2A), as described previously (15). In comparison, cyclophosphamide-pretreated WT mice exhibited clear signs of pollakisuria, characterized by a doubling of the voiding frequency and an ∼50% reduction of the voided volume ( Fig.…”

“…Recent research has shown that TRPV4, a cation channel of the transient receptor potential (TRP) superfamily (10,11), is highly expressed in the urothelial cell layer of the bladder, where it is implicated in sensing the filling state of the bladder (12)(13)(14)(15)(16). Importantly, Trpv4 −/− mice exhibited a lower voiding frequency and larger voided volume than wild type (WT) mice did.…”