Clinical Medicine Postdoctoral Research Station, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Department of Urology, The General Hospital of Western Theater Command, Chengdu, China.
Kaohsiung J Med Sci. 2022 Sep;38(9):879-888. doi: 10.1002/kjm2.12569. Epub 2022 Jun 29.
Urotensin II (U-II) and its receptor (UT) are involved in the pathogenesis of various diseases; however, their association with the development of cystitis has not been elucidated. The present study was designed to investigate the functional role of U-II/UT signaling in cyclophosphamide (CYP)-induced cystitis. A total of 60 female rats were randomly divided into the control and CYP-treated groups. Intraperitoneal injection of CYP successfully induced cystitis in rats of the CYP-treated group. The protein and mRNA expression levels of U-II and UT were significantly enhanced in rat bladder tissues of the CYP-treated group. Furthermore, the results of the immunofluorescence staining analysis demonstrated that CYP treatment apparently increased the expression levels of UT in the urothelium layer, detrusor smooth muscle, and bladder interstitial Cajal-like cells. The selective antagonist of UT, SB657510 (10 μm), significantly suppressed the CYP-induced increase in the spontaneous contractions of muscle strips and ameliorated the bladder hyperactivity of CYP-treated rats. Moreover, CYP treatment significantly increased the protein expression levels of Ras homolog family member (Rho) A and Rho-associated protein kinase 2 in rat bladder tissues. Following pretreatment with the Rho-kinase inhibitor Y-27632 (10 μm), the inhibitory effects of SB657510 (10 μm) on the spontaneous contractions of muscle strips were eliminated. In conclusion, the results of the present study suggested that activation of U-II/UT signaling promoted the development of cystitis-associated-bladder hyperactivity by targeting the RhoA/Rho-kinase pathway, indicating that the U-II/UT signaling could serve as a novel target for the treatment of interstitial cystitis/bladder pain syndrome.
尿促素 II（U-II）及其受体（UT）参与多种疾病的发病机制，但它们与膀胱炎的发展之间的关系尚未阐明。本研究旨在探讨 U-II/UT 信号在环磷酰胺（CYP）诱导的膀胱炎中的功能作用。将 60 只雌性大鼠随机分为对照组和 CYP 处理组。腹腔注射 CYP 成功地诱导了 CYP 处理组大鼠的膀胱炎。CYP 处理组大鼠膀胱组织中 U-II 和 UT 的蛋白和 mRNA 表达水平显著增强。此外，免疫荧光染色分析的结果表明，CYP 处理明显增加了 UT 在尿路上皮层、逼尿肌平滑肌和膀胱间充质 Cajal 样细胞中的表达水平。UT 的选择性拮抗剂 SB657510（10 μm）显著抑制了 CYP 诱导的肌肉条自发收缩的增加，并改善了 CYP 处理大鼠的膀胱过度活动。此外，CYP 处理显著增加了大鼠膀胱组织中 Ras 同源家族成员（Rho）A 和 Rho 相关蛋白激酶 2 的蛋白表达水平。在用 Rho 激酶抑制剂 Y-27632（10 μm）预处理后，SB657510（10 μm）对肌肉条自发收缩的抑制作用被消除。综上所述，本研究结果表明，U-II/UT 信号的激活通过靶向 RhoA/Rho 激酶通路促进了与膀胱炎相关的膀胱过度活动的发展，表明 U-II/UT 信号可作为治疗间质性膀胱炎/膀胱疼痛综合征的新靶点。
