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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 J+Physiol
2016 ; 594
(13
): 3575-88
Nephropedia Template TP
J Physiol
2016[Jul]; 594
(13
): 3575-88
PMID27006168
show ga
KEY POINTS: The sensory components of the urinary bladder are responsible for the
transduction of bladder filling and are often impaired with neurological injury
or disease. Elevated extracellular ATP contributes, in part, to bladder afferent
nerve hyperexcitability during urinary bladder inflammation or irritation.
Transforming growth factor-?1 (TGF-?1) may stimulate ATP release from the
urothelium through vesicular exocytosis mechanisms with minimal contribution from
pannexin-1 channels to increase bladder afferent nerve discharge. Bladder
afferent nerve hyperexcitability and urothelial ATP release with CYP-induced
cystitis is decreased with TGF-? inhibition. These results establish a causal
link between an inflammatory mediator, TGF-?, and intrinsic signalling mechanisms
of the urothelium that may contribute to the altered sensory processing of
bladder filling. ABSTRACT: The afferent limb of the micturition reflex is often
compromised following bladder injury, disease and inflammatory conditions. We
have previously demonstrated that transforming growth factor-? (TGF-?) signalling
contributes to increased voiding frequency and decreased bladder capacity with
cystitis. Despite the functional presence of TGF-? in bladder inflammation, the
precise mechanisms of TGF-? mediating bladder dysfunction are not yet known.
Thus, the present studies investigated the sensory components of the urinary
bladder that may underlie the pathophysiology of aberrant TGF-? activation. We
utilized bladder-pelvic nerve preparations to characterize bladder afferent nerve
discharge and the mechanisms of urothelial ATP release with distention. Our
findings indicate that bladder afferent nerve discharge is sensitive to elevated
extracellular ATP during pathological conditions of urinary bladder inflammation
or irritation. We determined that TGF-?1 may increase bladder afferent nerve
excitability by stimulating ATP release from the urothelium via vesicular
exocytosis mechanisms with minimal contribution from pannexin-1 channels.
Furthermore, blocking aberrant TGF-? signalling in cyclophosphamide-induced
cystitis with T?R-1 inhibition decreased afferent nerve hyperexcitability with a
concomitant decrease in urothelial ATP release. Taken together, these results
establish a role for purinergic signalling mechanisms in TGF-?-mediated bladder
afferent nerve activation that may ultimately facilitate increased voiding
frequency. The synergy between intrinsic urinary bladder signalling mechanisms
and an inflammatory mediator provides novel insight into bladder dysfunction and
supports new avenues for therapeutic intervention.
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