β-Adrenoceptors regulate matrix metalloproteinase expression in human urothelial cells under hydrostatic pressure
β-Adrenoceptors regulate matrix metalloproteinase expression in human urothelial cells under hydrostatic pressure
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β-肾上腺素能受体在静水压下调节人尿路上皮细胞基质金属蛋白酶的表达
DOI：
10.1002/nau.24362
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发表时间：
2020-04-24
影响因子：
2
通讯作者：
Wang, Kunjie
中科院分区：
文献类型：
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作者：
Lan, Jianhua;Jin, Tao;Wang, Kunjie
在膀胱充盈和排尿周期中，膀胱壁不断受到膀胱内压力。膀胱内压力升高时基质金属蛋白酶（MMPs）和组织金属蛋白酶抑制剂（TIMPs）之间的失衡导致膀胱病理改变。为了研究膀胱内压力升高下人类尿路上皮细胞（huc）的变化，本研究分析了β -肾上腺素能受体信号传导对huc暴露于病理静水压力（HP） （70 cm H2O） 6小时后MMPs和TIMPs表达的影响。采用定量聚合酶链反应、Western blot分析和细胞荧光染色方法，探讨受体受体信号传导对激动剂和/或拮抗剂处理后hus中MMPs和TIMPs表达的影响。β(2)-和β(3)-肾上腺素受体、MMP1和MMP2的表达水平大幅下调，TIMP1的表达大幅上调。福莫特罗和BRL 37344分别是β(2)-和β(3)-肾上腺素能受体的激动剂，在70 cm H2O下显著增加MMP1和MMP2的表达。作为β(2)-和β(3)-肾上腺素能受体的经典下游通路，蛋白激酶a（PKA）信号通过调节cAMP反应元件结合蛋白（CREB）活性来抑制MMP1和MMP2的表达。β(2)-和β(3)-肾上腺素受体通过PKA/CREB途径修饰hus中70 cm H2O下MMP1和MMP2的表达。这一结果表明MMPs可能参与了膀胱内压力升高的病理作用。β(2)-和β(3)-肾上腺素能受体在膀胱内压力升高中的潜在机制也被揭示；这一机制为部分膀胱出口梗阻的治疗提供了新的潜在靶点。
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.