Inhibition of U‐II/UT signaling ameliorates cystitis‐associated bladder hyperactivity by targeting the RhoA/Rho‐kinase pathway

Abstract 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.