Induction of oxidative stress causes functional alterations in mouse urothelium via a TRPM8‐mediated mechanism: implications for aging

Abstract

The incidence of bladder conditions such as overactive bladder syndrome and its associated urinary incontinence is highly prevalent in the elderly. However, the mechanisms underlying these disorders are unclear. Studies suggest that the urothelium forms a ‘sensory network’ with the underlying innervation, alterations in which, could compromise bladder function. As the accumulation of reactive oxygen species can cause functional alterations with age, the aim of this study was to investigate whether oxidative stress alters urothelial sensory signalling and whether the mechanism underlying the effect of oxidative stress on the urothelium plays a role in aging. Five-month-old(young) and 24-month-old (aged) mice were used. H2O2, used to induce oxidative stress, resulted in an increase in bladder afferent nerve activity and urothelial intracellular calcium in preparations from young mice. These functional changes were concurrent with upregulation of TRPM8 in the urothelium. Moreover, application of a TRPM8 antagonist significantly attenuated the H2O2-induced calcium responses. Interestingly, an upregulation of TRPM8 was also found in the urothelium from aged mice, where high oxidative stress levels were observed, together with a greater calcium response to the TRPM8 agonist WS12. Furthermore, these calcium responses were attenuated by pretreatment with the antioxidant N-acetyl-cysteine. This study shows that oxidative stress affects urothelial function involving a TRPM8-mediated mechanism and these effects may have important implications for aging. These data provide an insight into the possible mechanisms by which oxidative stress causes physiological alterations in the bladder, which may also occur in other organs susceptible to aging.

Hydrogen peroxide preferentially activates capsaicin‐sensitive high threshold afferents via TRPA1 channels in the guinea pig bladder

“…Excessive ROS production occurs in many pathological conditions including inflammation and reperfusion after ischaemia, contributing to the pathogenesis of a variety of human diseases (Comhair and Erzurum, ). In the bladder, excess production of ROS is strongly implicated in overactive bladder syndrome, bladder obstruction and pathological conditions developed with age (Brading et al, ; Nomiya et al, ; Nocchi et al, ). Excessive chronic generation of ROS during ischaemia‐reperfusion causes suppression of detrusor muscle function, inhibition of bladder afferents and efferents, and patchy nerve degeneration in the detrusor in patients with bladder obstruction and in animal models of obstruction and over‐distension (Brading et al, ; Yu et al, ; Scheepe et al, ).…”

“…In the bladder, TRPM8 channels are expressed in the urothelium and in sensory nerve fibres (Stein et al, ; Mukerji et al, ; Hayashi et al, ). In the urothelium, TRPM8 channels may respond to the increased levels of ROS associated with ageing (Nocchi et al, ). We found that 47% of capsaicin‐sensitive high threshold afferents were activated by the TRPM8 channel agonist icilin.…”

The application of mesenchymal progenitor stem cells for the reduction of oxidative stress in animals

“…However, Chan et al (2001) showed deficiency of the p45NF-E2 gene, which causes an accumulation of elevated levels of reactive oxygen intermediates in red blood cells. According to Nocchi et al (2014), one of the main symptoms of oxidative stress in mice is impaired bladder activity associated with the deterioration of contractile response. Under conditions of ROS overproduction induced by the addition of melamine to the diet of female mice, Dai et al (2015) reported ovarian damage in the form of abnormal oocyte maturation.…”

Lower Urinary Tract Symptoms and Aging: The Impact of Chronic Bladder Ischemia on Overactive Bladder Syndrome

“…In agreement with this hypothesis, Nocchi et al [21] served that intravesical administration of H 2 O 2 in normal rats induced bladder overactivity, as shown by a reduction in the intercontraction interval between detrusor contractions. Also in rats, Homan et al [23] observed that a single intravesical injection of H 2 O 2 significantly increased the number of voids, which lasted up to 7 days.…”