Loss of Dicer Exacerbates Cyclophosphamide-Induced Bladder Overactivity by Enhancing Purinergic Signaling
Loss of Dicer Exacerbates Cyclophosphamide-Induced Bladder Overactivity by Enhancing Purinergic Signaling
复制标题
Dicer 的缺失通过增强嘌呤能信号加剧环磷酰胺诱导的膀胱过度活动
DOI：
10.1016/j.ajpath.2012.05.035
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发表时间：
2012-09-01
影响因子：
6
通讯作者：
Wang, Cong-Yi
中科院分区：
文献类型：
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作者：
Zhang, Shu;Lv, Jian-Wei;Wang, Cong-Yi
microRNA（miRNAs）调节了许多病理环境中涉及的基因的表达和功能，但它们对膀胱过度活动症（OAB）的病理病因学特征的影响在很大程度上仍然未知。我们已经建立了一个小鼠模型，其中成年小鼠可以诱导逼尿肌Dicer缺失，Dicer是miRNA加工所必需的酶。Dicer的靶向缺失在生理条件下不会导致逼尿肌功能的显著变化;然而，Dicer的缺失加剧了环磷酰胺诱导的OAB，表现为逼尿肌收缩力和敏感性改变、尿动力学异常和巨噬细胞浸润增强的严重程度更高。机制研究表明，Dicer的缺失可能会损害能够靶向P2 x mRNA的miRNA的表达。因此，Dicer缺陷的小鼠在环磷酰胺治疗后逼尿肌中表现出增强的P2 X表达，易患OAB发展的风险增加。更重要的是，使用OAB患者膀胱活检样本的研究也显示了与动物相似的结果。综上所述，我们的研究结果表明，miRNAs通过调节嘌呤能信号传导来调节OAB易感性，其中致病性损伤诱导能够靶向P2 X mRNA的miRNAs的表达以抑制OAB症状。(Anti Pathol 2012，181：937-946。http://dx.doi.org/10.1016/j.ajpath.2012.05.035)
microRNAs (miRNAs) have regulated the expression and function of genes implicated in many pathological settings, but their impact on the pathoetiological characteristics of overactive bladder (OAB) largely remains unknown. We have generated a mouse model in which adult mice can be induced for detrusor deletion of Dicer, an enzyme essential for miRNA processing. Targeted deletion of Dicer did not lead to a significant change for detrusor functionality under physiological conditions; however, loss of Dicer exacerbated cyclophosphamide-induced OAB, manifested by the higher severity of altered detrusor contractile force and sensitivity, abnormal urodynamics, and enhanced macrophage infiltration. Mechanistic studies revealed that loss of Dicer may impair the expression of miRNAs that are capable of targeting P2x mRNAs. As a result, mice deficient in Dicer manifest enhanced P2X expression in the detrusor on cyclophosphamide treatment, predisposing to the increased risk for OAB development. More important, studies using bladder biopsy samples of patients with OAB also demonstrated similar results as those found in animals. Taken together, our results suggest that miRNAs modulate OAB susceptibility by regulating purinergic signaling, in which the pathogenic insult induces the expression of miRNAs capable of targeting P2X mRNAs to suppress OAB symptoms. (Anti Pathol 2012, 181:937-946. http://dx.doi.org/10.1016/j.ajpath.2012.05.035)