Beta-Adrenoceptors Regulate Matrix Metalloproteinase Expression In Human Urothelial Cells Under Hydrostatic Pressure

The bladder wall is constantly subjected to intravesical pressure during the filling and voiding cycles. An imbalance between matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) under elevated intravesical pressure contributes to pathological changes in the bladder. To investigate the changes in human urothelial cells (HUCs) under elevated intravesical pressure, this study analyzed the effect of beta-adrenoceptor signaling on the expression of MMPs and TIMPs in HUCs exposed to pathological hydrostatic pressure (HP) (70 cm H2O) for 6 hours. Quantitative polymerase chain reaction, Western blot analysis, and cell fluorescence staining were used to explore the effect of beta-adrenoceptor signaling on the expression of MMPs and TIMPs in HUCs after agonist and/or antagonist treatment. The expression levels of beta(2)- and beta(3)-adrenoceptor, MMP1, and MMP2 were greatly downregulated, while the expression of TIMP1 was greatly upregulated. Formoterol and BRL 37344, which are agonists of beta(2)- and beta(3)-adrenoceptor, respectively, significantly increased MMP1 and MMP2 expression under 70 cm H2O. As a classic downstream pathway of beta(2)- and beta(3)-adrenoceptor, protein kinase A (PKA) signaling inhibited MMP1 and MMP2 expression by regulating cAMP response element binding protein (CREB) activity. MMP1 and MMP2 expression in HUCs under 70 cm H2O was modified by beta(2)- and beta(3)-adrenoceptor via the PKA/CREB pathway. This outcome suggests that MMPs likely participate in the pathological effects of elevated intravesical pressure. The underlying mechanism of beta(2)- and beta(3)-adrenoceptor in elevated intravesical pressure was also revealed; this mechanism constitutes a new potential therapeutic target for partial bladder outlet obstruction.