Regulation of Cellular Stress Signaling in Bladder Ischemia.
Regulation of Cellular Stress Signaling in Bladder Ischemia.
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DOI：
10.2147/rru.s271618
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发表时间：
2020
影响因子：
1.6
通讯作者：
Azadzoi K
中科院分区：
文献类型：
--
作者：
Yang JH;Li Y;Azad R;Azadzoi K
非梗阻性非神经源性膀胱患者下尿路症状的病因在很大程度上仍然未知。临床研究揭示了膀胱血流量减少和膀胱顺应性低之间的显着相关性。膀胱缺血的动物模型显示结构改变，其特征在于平滑肌细胞的损失和结缔组织在膀胱壁中的积累。膀胱缺血导致结构损伤的潜在机制仍然很难理解。我们以前报道过膀胱缺血的结构改变与上调的应激蛋白和细胞存活信号相关，提示细胞应激在缺血性损伤中的潜在作用。然而，应激反应分子和下游途径引起膀胱缺血损伤仍然在很大程度上不确定。采用大鼠膀胱缺血沿着细胞培养缺氧模型，研究缺血膀胱组织和缺氧膀胱平滑肌细胞中的应激信号分子。我们的数据表明，同时上调两个主要的细胞应激传感分子，即凋亡信号调节激酶1（ASK 1）和caspase-3，这意味着退行性损伤通过应力信号通路在膀胱缺血。与膀胱缺血一致，培养的人膀胱平滑肌细胞在低氧张力下孵育增加了ASK 1和caspase-3的表达，暗示缺氧是ASK 1和caspase-3上调的重要因素。在培养的平滑肌细胞中通过ASK 1 siRNA缺失ASK 1基因阻止了缺氧引起的caspase-3上调，表明在缺血/缺氧条件下ASK 1对caspase-3的调节。在大鼠膀胱缺血和人膀胱平滑肌细胞缺氧中，ASK 1和caspase-3的上调与凋亡损伤的初始阶段一致的亚细胞结构修饰相关。我们的数据表明，ASK 1和caspase-3的压力传感可能有助于亚细胞结构损伤和低膀胱顺应性。ASK 1/caspase-3通路可能为膀胱缺血中细胞应激和退行性反应提供治疗靶点。
The etiology of lower urinary tract symptoms in patients with non-obstructed non-neurogenic bladder remains largely unknown. Clinical studies divulged a significant correlation between reduced bladder blood flow and low bladder compliance. Animal models of bladder ischemia displayed structural modifications, characterized by loss of smooth muscle cells and accumulation of connective tissue in the bladder wall. The underlying mechanisms contributing to structural damage in bladder ischemia remain largely elusive. We previously reported that structural modifications in bladder ischemia correlate with upregulated stress proteins and cell survival signaling, suggesting the potential role of cellular stress in ischemic damage. However, stress response molecules and downstream pathways eliciting bladder damage in ischemia remain largely undetermined. Using a rat model of bladder ischemia along with a cell culture hypoxia model, we investigated stress signaling molecules in the ischemic bladder tissues and hypoxic bladder smooth muscle cells. Our data suggest simultaneous upregulation of two major cellular stress-sensing molecules, namely apoptosis signal-regulating kinase 1 (ASK1) and caspase-3, implying degenerative insult via stress signaling pathway in bladder ischemia. Consistent with bladder ischemia, incubation of cultured human bladder smooth muscle cells at low oxygen tension increased both ASK1 and caspase-3 expression, insinuating hypoxia as an essential factor in ASK1 and caspase-3 upregulation. Gene deletion of ASK1 by ASK1 siRNA in cultured smooth muscle cells prevented caspase-3 upregulation by hypoxia, suggesting caspase-3 regulation by ASK1 under the ischemic/hypoxic conditions. Upregulation of ASK1 and caspase-3 in rat bladder ischemia and human bladder smooth muscle cell hypoxia was associated with subcellular structural modifications consistent with the initial stages of apoptotic insult. Our data suggest that stress sensing by ASK1 and caspase-3 may contribute to subcellular structural damage and low bladder compliance. The ASK1/caspase-3 pathway may provide therapeutic targets against cellular stress and degenerative responses in bladder ischemia.