Department of Pharmacology, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Box 431, 405 30 Gothenburg, Sweden.
Auton Neurosci. 2018 Sep;213:60-70. doi: 10.1016/j.autneu.2018.06.001. Epub 2018 Jun 6.
Cholesterol rich membrane invaginations, caveolae, have important roles in various cellular activities, one of them being signal transduction. This signaling pathway seems to be affected during various bladder disorders and the current study aimed to elucidate the plausible involvement of caveolae mediated signal transduction during cyclophosphamide induced cystitis. Furthermore, the urothelial cholinergic part of ATP-evoked contractions and its possible link to caveolae were investigated. Cholinergic, as well as purinergic, contractile responses in rat urinary bladders were examined using a classic organ bath set-up with full-thickness strip preparations or a whole bladder model that enabled luminal administration of substances. Furthermore, sub groups with and without urothelium were examined. The expression of caveolin-1 was also tested using western blot and immunofluorescence. Caveolae cholesterol depletion by methyl-β-cyclodextrin entailed a significant decrease of ATP-evoked bladder contractility. Interestingly, after muscarinic blockade the ATP induced contractions were significantly reduced in the same manner. Furthermore, this atropine-sensitive part of ATP-evoked responses was absent in denuded as well as inflamed bladders. A tendency towards a reduced expression of caveolin-1 was observed in rats with experimental cystitis. The cholinergic part of ATP-induced contractile responses seemed to be affected by urothelium denudation as well as caveolae depletion. Removing one of these structures nullifies the effect of the other, suggesting an important interaction between the urothelium and the caveolar structures. These effects are absent in inflamed animals and might be one pathophysiological aspect behind BPS/IC.
富含胆固醇的膜内陷，即 caveolae，在各种细胞活动中具有重要作用，其中之一是信号转导。这种信号通路似乎在各种膀胱疾病中受到影响，本研究旨在阐明 caveolae 介导的信号转导在环磷酰胺诱导的膀胱炎中的可能作用。此外，还研究了 caveolae 介导的信号转导在尿路上皮乙酰胆碱能部分诱导的 ATP 收缩及其可能的联系。使用经典器官浴装置和全层条带制剂或允许腔内给药的整个膀胱模型，检查了大鼠膀胱中的胆碱能和嘌呤能收缩反应。此外，还检查了有无尿路上皮的亚组。还使用 Western blot 和免疫荧光法测试了 caveolin-1 的表达。甲基-β-环糊精耗尽 caveolae 胆固醇会显著降低 ATP 诱导的膀胱收缩性。有趣的是，在阻断毒蕈碱受体后，ATP 诱导的收缩以相同的方式显著减少。此外，在去上皮和发炎的膀胱中，这种对 ATP 诱导反应的毒蕈碱敏感部分也不存在。在实验性膀胱炎大鼠中观察到 caveolin-1 的表达有下降的趋势。ATP 诱导的收缩的胆碱能部分似乎受到尿路上皮去上皮和 caveolae 耗竭的影响。去除这些结构中的一种会使另一种结构的作用失效，这表明尿路上皮和 caveolar 结构之间存在重要的相互作用。这些效应在发炎动物中不存在，可能是 BPS/IC 的一个病理生理方面。
