TRPA1 channel mediates methylglyoxal-induced mouse bladder dysfunction

Abstract

Introduction: The transient receptor potential ankyrin 1 channel (TRPA1) is expressed in urothelial cells and bladder nerve endings. Hyperglycemia in diabetic individuals induces accumulation of the highly reactive dicarbonyl compound methylglyoxal (MGO), which modulates TRPA1 activity. Long-term oral intake of MGO causes mouse bladder dysfunction. We hypothesized that TRPA1 takes part in the machinery that leads to MGO-induced bladder dysfunction. Therefore, we evaluated TRPA1 expression in the bladder and the effects of 1 h-intravesical infusion of the selective TRPA1 blocker HC-030031 (1 nmol/min) on MGO-induced cystometric alterations.Methods: Five-week-old female C57BL/6 mice received 0.5% MGO in their drinking water for 12 weeks, whereas control mice received tap water alone.Results: Compared to the control group, the protein levels and immunostaining for the MGO-derived hydroimidazolone isomer MG-H1 was increased in bladders of the MGO group, as observed in urothelium and detrusor smooth muscle. TRPA1 protein expression was significantly higher in bladder tissues of MGO compared to control group with TRPA1 immunostaining both lamina propria and urothelium, but not the detrusor smooth muscle. Void spot assays in conscious mice revealed an overactive bladder phenotype in MGO-treated mice characterized by increased number of voids and reduced volume per void. Filling cystometry in anaesthetized animals revealed an increased voiding frequency, reduced bladder capacity, and reduced voided volume in MGO compared to vehicle group, which were all reversed by HC-030031 infusion.Conclusion: TRPA1 activation is implicated in MGO-induced mouse overactive bladder. TRPA1 blockers may be useful to treat diabetic bladder dysfunction in individuals with high MGO levels.

Methylglyoxal and Advanced Glycation End Products (AGEs): Targets for the Prevention and Treatment of Diabetes-Associated Bladder Dysfunction?

“…Using the model of spontaneous void spot assay (VSA) on filter paper, male mice treated with MGO for 12 weeks revealed an increased volume per void with no changes in the spot number as compared with the untreated group. In the female group, this treatment increased the spot number (mainly the number of microvolume spots) but, rather, reduced the volume per void [177,180]. During the MGO treatment, no alterations in the water consumption are observed in any group [177].…”

“…An increased carbachol-induce response by MGO treatment in the female mice is solely observed when the urothelium is removed from the preparations. Moreover, the higher EFS-induced contractions in the MGO group were normalized by prior tissue incubation with the selective TRPA1 blocker HC-030031, suggesting that MGO exposure via TRPA1 activation leads to enhancement of purinergic over cholinergic neurotransmission in the bladder [180] (Figure 2). Table 2 summarizes the main in vivo and in vitro bladder alterations observed in male and female mice treated with MGO for 12 weeks.…”