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.
Highlights
The lower urinary tract and its innervation appear to be susceptible to aging such that the incidence of bladder-relatedAccepted for publication 5 January 2014 symptoms, as seen in overactive bladder syndrome (OAB) and in particular urinary incontinence (UI), increases in the elderly; the aetiology of these bladder disorders is still not defined
The aim of this study was to investigate whether oxidative stress alters urothelial sensory signalling in the bladder and whether the mechanism underlying the effect of oxidative stress on the urothelium plays a role in aging
We reported significant changes in bladder function as a result of aging, which were indicative of bladder hypersensitivity and hyperactivity; an increase in urothelial cell excitability and transmitter release was found, supporting the hypothesis that the urothelial sensory signalling is altered as a result of aging (Daly et al, 2014)
Summary
The lower urinary tract and its innervation appear to be susceptible to aging such that the incidence of bladder-relatedAccepted for publication 5 January 2014 symptoms, as seen in overactive bladder syndrome (OAB) and in particular urinary incontinence (UI), increases in the elderly; the aetiology of these bladder disorders is still not defined. Studies suggest that in addition to its barrier function, the urothelium is a dynamic structure that actively contributes to the sensory function of the bladder via the release of excitatory and inhibitory mediators in response to mechanical and chemical stimuli. Studies suggest that alterations to urothelial structure and compromised urothelial sensory signalling could underlie several bladder disorders (Birder et al, 2012). Experimental studies in rodents suggest that aging impairs contractile response in the bladder, and this effect correlates with an increase in oxidative stress markers, suggesting that oxidative stress may contribute to alter bladder function in aging (Gomez-Pinilla et al, 2007b). The hypothesis that an age-related accumulation of ROS can affect bladder function is strengthened by several studies showing that treatment with antioxidants, such as melatonin and green tea catechins, can improve bladder physiology (Gomez-Pinilla et al, 2007a,b, 2008; Juan et al, 2012). The mechanisms underlying the effect of oxidative stress on bladder function are still unclear
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