Pathophysiological Role of Transient Receptor Potential Ankyrin 1 in a Mouse Long-Lasting Cystitis Model Induced by an Intravesical Injection of Hydrogen Peroxide

Abstract

Chronic inflammatory bladder disorders, such as interstitial cystitis/bladder pain syndrome, are associated with poor quality of life. The exact pathological processes remain unclear, but accumulating evidence suggests that reactive oxidative species (ROS) are involved in urinary bladder disorders. Transient receptor potential ankyrin 1 (TRPA1), the most sensitive TRP channel to ROS, was shown to be responsible for urinary bladder abnormalities and hyperalgesia in an acute cystitis model. However, the roles of TRPA1 in chronic inflammatory bladder are not fully understood. We previously established a novel mouse cystitis model induced by intravesical injection of hydrogen peroxide (H2O2), resulting in long-lasting frequent urination, bladder inflammation, pain-related behavior, and histopathological changes. In the present study, we investigated the pathophysiological role of TRPA1 in the H2O2-induced long-lasting cystitis mouse model. Under anesthesia, 1.5% H2O2 solution was introduced transurethrally into the bladder of female wild-type (WT) and TRPA1-knockout mice and maintained for 30 min. This increased the number of voids in WT mice at 1 and 7 days after injection, but reduced the number in TRPA1-knockout mice at 1 day but not 7 days after injection. Spontaneous locomotor activities (increase in freezing time and decrease in distance moved) were reduced at 3 h after injection in WT mice, whereas the spontaneous visceral pain-related behaviors were attenuated in TRPA1-knockout mice. Furthermore, upregulation of c-fos mRNA in the spinal cord at 1 day after injection was observed in WT but not TRPA1-knockout mice. However, there was no difference in histopathological changes in the urinary bladder, such as edematous thickening in the submucosa, between WT and TRPA1-knockout mice at 1 or 7 days after injection. Finally, Trpa1 mRNA levels in the L5-S1 dorsal root ganglion were not altered, but levels in the urinary bladder were drastically increased at 1 and 7 days after injection. Taken together, these results suggest that TRPA1 contributes to acute bladder hyperactivity such as frequent urination and bladder pain, but does not appear to play a major role in the pathological processes of long-lasting cystitis.

Mammalian Transient Receptor Potential TRPA1 Channels: From Structure to Disease

“…Agonists of TRPA1 (AITC and CA) increase the bladder contraction, stretch sensitivity, hyperalgesia, and micturition in rats and guinea pigs (37,193,222,589). Moreover, in various OAB models, TRPA1 protein and mRNA expression levels are increased in the bladder and in the DRG neurons innervating it (38,193,221,376,499,539,634,862). This upregulated TRPA1 expression may increase sensory transductions and induce the OAB symptoms.…”

Hyperbaric oxygen significantly improves frequent urination, hyperalgesia, and tissue damage in a mouse long‐lasting cystitis model induced by an intravesical instillation of hydrogen peroxide

“…Several subtypes of TRP channels are reportedly major components of the sensory system controlling bladder function in response to diverse stimuli . In rodent cystitis models with nociceptive pain derived from acroline, the metabolite of cyclophosphamide, or H 2 O 2 , the function and/or expression of TRPA1, TRPV1, and TRPV4 has been shown to be accelerated . In this study, expression of TRPV1 and TRPV4 in the mouse bladder submucosa and/or urothelium was induced by oxidative stress from H 2 O 2 , and change in expression was clearly inhibited by HBO treatment (Figure ).…”

“…However, there was no significant change in TRPA1 expression in bladder between the sham control and H 2 O 2 ‐treated group (data not shown). This molecule is also focused as a key factor to generate pain and cause bladder dysfunction in response to numerous irritants and ROS, while the alteration in TRPA1 expression under an exposure to H 2 O 2 in this study might be remarkable in the C‐fiber afferent pathway (ie, pelvic dorsal root ganglion) rather than bladder epithelium and submucosa. At least, the current results examined in bladder revealed that the inhibitory effect of HBO on TRP channel expression (eg, TRPV1, TRPV4) could partially contribute to improved voiding function and bladder‐related pain in this chronic cystitis model.…”

Methylglyoxal, a Reactive Glucose Metabolite, Induces Bladder Overactivity in Addition to Inflammation in Mice

“…TRP channels are widely expressed in lower urinary tract tissues and play a critical role in the normal micturition reflex (for review: Andersson, 2019). TRPA1 is known to contribute to nociceptive responses evoked by endogenous and exogenous irritants (Oyama et al, 2017), including MGO itself (Bierhaus et al, 2012;Eberhardt et al, 2012). On the other hand, TRPV1 and TRPV4 are involved in bladder activity in response to mechanical or chemical stimulus (Andersson, 2019).…”