Gheinani Ali Hashemi, Köck Ivonne, Vasquez Evalynn, Baumgartner Ulrich, Bigger-Allen Alexander, Sack Bryan S, Burkhard Fiona C, Adam Rosalyn M, Monastyrskaya Katia
Department of Urology, Boston Children's Hospital Boston, MA, USA.
Department of Surgery, Harvard Medical School Boston, MA, USA.
Am J Clin Exp Urol. 2018 Dec 20;6(6):219-233. eCollection 2018.
Bladder outlet obstruction (BOO) leads to lower urinary tract symptoms (LUTS) and urodynamic changes of the bladder function. Previously we identified microRNA (miRNA) and mRNA expression profiles associated with different states of BOO-induced LUTD in human patients. Bladder wall remodeling resulting from obstruction is widely studied in animal models of experimentally-induced partial BOO (pBOO). Here we determined the expression profiles of miRNAs and selected mRNAs in pBOO mice and compared the observed changes to human patients. Similar to results from human patients, we observed a down-regulation of smooth muscle-associated miRNAs mmu-miR-1, mmu-miR-143, mmu-miR-145, mmu-miR-486 and mmu-miR-133a in pBOO mouse bladders. Pro-fibrotic miRNAs mmu-miR-142-3p and mmu-miR-21 were up-regulated, and anti-fibrotic miRNA mmu-miR-29c was down-regulated. Pathway analysis in human BOO patients identified TNF-alpha as the top upstream regulator. Although there was evidence of hypertrophic changes in pBOO mice, contrary to human data, we observed no regulation of TNF-responsive genes in the mouse model. Experimentally-induced pBOO in mice led to significant gene expression changes, including alteration of pro-fibrotic mRNAs and miRNAs resembling human BOO patients. Gene expression changes were also validated in a mouse model of bladder inflammation. Lack of evidence of TNF-alpha-induced miRNA and mRNA regulation might indicate a different pathophysiological mechanism of organ remodeling in pBOO model compared to the human disease.
膀胱出口梗阻（BOO）会导致下尿路症状（LUTS）以及膀胱功能的尿动力学改变。此前我们已确定了与人类患者BOO诱导的下尿路疾病（LUTD）不同状态相关的微小RNA（miRNA）和信使核糖核酸（mRNA）表达谱。在实验性诱导的部分膀胱出口梗阻（pBOO）动物模型中，对梗阻导致的膀胱壁重塑进行了广泛研究。在此，我们确定了pBOO小鼠中miRNA和选定mRNA的表达谱，并将观察到的变化与人类患者进行了比较。与人类患者的结果相似，我们观察到pBOO小鼠膀胱中与平滑肌相关的miRNA，即小鼠miR-1、小鼠miR-143、小鼠miR-145、小鼠miR-486和小鼠miR-133a表达下调。促纤维化miRNA小鼠miR-142-3p和小鼠miR-21上调，而抗纤维化miRNA小鼠miR-29c下调。对人类BOO患者的通路分析确定肿瘤坏死因子-α（TNF-α）为首要上游调节因子。尽管有证据表明pBOO小鼠存在肥大性改变，但与人类数据相反，我们在小鼠模型中未观察到TNF反应基因的调控。实验性诱导小鼠发生pBOO会导致显著的基因表达变化，包括促纤维化mRNA和miRNA的改变，类似于人类BOO患者。基因表达变化在膀胱炎症小鼠模型中也得到了验证。缺乏TNF-α诱导的miRNA和mRNA调控的证据可能表明，与人类疾病相比，pBOO模型中器官重塑的病理生理机制有所不同。
