Age associated changes in urothelium-dependent ATP release- advancing understanding of Overactive Bladder Syndrome (OAB) pathophysiology
Creators: name: Gurpinar, Ayse
Publisher: name: Zenodo
Year: 2021

description: Overactive bladder syndrome (OAB) is a global chronic condition that can be characterised by frequent urge for urination with or without incontinence [1]. It is well documented that, OAB dramatically increases with age for both sexes and significantly impacts on patient’s quality of life [2]. Therefore, growing elderly population is increasing the OAB-related financial strain on health services [3]. It is vital to advance current understanding of OAB to develop effective treatments. The principle aetiology of OAB has yet to be identified [1]. However, as a key regulator of urinary bladder sensation, disturbed extracellular ATP signalling is believed to contribute to pathophysiology of OAB [4]. Indeed, increased stretch-induced urothelial ATP release has been reported from human OAB-positive bladder biopsies [5]. Here, we focus on the inflammatory mediator evoked ATP release in young and aging bladders. We hypothesise that, there is a disturbed ATP release due to age-dependent changes in underlying pathways.<br> Young (12-33 weeks) and aged (&gt;80weeks) male C57BL/6 wild type mice were used. Bladders were harvested according to UK/EU regulations and longitudinal full thickness tissue strips were prepared via microdissection for functional organ bath experimentation. Superfusate samples were collected and tested for ATP content using Luciferin-Luciferase assay. Data are expressed as median±interquartile range and tested by Wilcoxon’s test (nonparametric).<br> The most extensively investigated tachykinin Substance P (SP)[6], evoked significant ATP release from both young and aging bladders with no difference between two groups (% change, young[n=10]: con - 8[5,19] SP - 11[7,27] *p&lt;0.05, aging[n=9]: con - 6[4,19] SP - 15[8,39] **p&lt;0.05). The pro-inflammatory cytokine Interleukin 1 alpha (IL-1α)[7] stimulated a significant ATP release from both young and aging bladders with no difference between two groups (% change, young[15]: con- 12[5,26] IL-1α- 14[6,43] **p&lt;0.05, aging[13]: con- 6[4,15] IL-1α- 18[4,31] *p&lt;0.05). The sarcoplasmic reticulum Ca²⁺ ATPase inhibitor Thapsigargin (TG)[8] caused a significant increase in ATP release in young but not aging (% change, young[n=13]: con- 11[8,14] TG- 15[7,20] * p&lt;0.05, aging[n=11] con-12[4,15] TG-9[6,20] ns p&gt;0.05). Perturbation of inflammation pathways by PKC inhibitor Staurosporine (STS) [9] caused significant ATP release in aged bladders only (% change, young[n=16]: con- 11[6,19] STS - 13[6,26] NS p&gt;0.05, aging[n=14]: con- 7[4,10] STS- 12[6,14] *p≤0.05).<br> Cellular pathways mediating the urothelial ATP release remains unclear. This is the first project to compare the effect of inflammation on ATP release in different age groups. This data suggests that aging seems to exhibit variations in some pathways as Thapsigargin evoked ATP release is lost in aging bladders and there is a potential dysregulation of PKC pathway in aged bladders. However, other important systems such as neuropeptides utilise similar pathway on both mice groups to trigger ATP release. To our knowledge, we have identified a novel activator for ATP release with IL-1α which also remains relevant for aging. Further research may reveal novel targets that could be manipulated to alleviate OAB.