Lu Yutao, Fog-Poulsen Kristian, Nørregaard Rikke, Djurhuus Jens Christian, Olsen L Henning
Department of Clinical Medicine, Aarhus University, Aarhus N, Denmark.
Department of Clinical Medicine, Aarhus University, Aarhus N, Denmark.
J Pediatr Urol. 2021 Apr;17(2):170.e1-170.e10. doi: 10.1016/j.jpurol.2020.12.026. Epub 2021 Jan 2.
Development of bladder fibrosis, loss of compliance, and voiding dysfunction are among the severe consequences of various lower urinary conditions, for example, bladder outlet obstruction (BOO), neurogenic bladder, and radiotherapy to the pelvic area. The bladder remodelling results in significant changes in bladder function and architecture, and may ultimately be deleterious for kidney function. The molecular signals underlying pathologic bladder remodelling, as well as the impact of gender, remain poorly understood.
To investigate the bladder remodelling after one day BOO, whether the remodelling is different between different bladder sections, and whether genders may affect the remodelling.
Thirty male and 30 female C57BL/6NRj mice were randomly divided into Control, Sham and BOO groups with ten mice per group. A 24-h total urethral obstruction was performed at the proximal urethra. Histological changes were observed via H&E, trichrome and immunohistochemistry staining. Harvested bladders were divided into upper and lower sections for analysis. Protein and gene expression were detected by Western blotting and qPCR.
No significant changes in bladder wall thickness were observed following BOO, while increased bladder mass after BOO was found in female mice only. We detected FN and ⍺-SMA upregulation in the male upper bladder segment. Female BOO mice bladders showed increased α-SMA expression in both bladder segments, but no difference of FN was observed in either bladder segments. BOO-induced upregulation of TGF-β and Gremlin were detected in both male and female bladders, while downregulation of BMP-7 was detected only in male bladders. Furthermore, phosphorylation of both SMAD2/3 and SMAD1/5/9 were increased in male bladders following BOO, whereas female mice exhibited increased pSMAD2/3 in the upper and increased pSMAD1/5/9 in the lower bladder segment.
Our data indicate that some specific proteins and growth factors were detected as early alterations of tissue which may lead to fibrosis. In addition, the males tended to have more pronounced response than females. However, the causes and consequences of the findings need to be further investigated.
膀胱纤维化、顺应性丧失和排尿功能障碍是各种下尿路疾病的严重后果，例如膀胱出口梗阻（BOO）、神经源性膀胱和盆腔放疗。膀胱重塑导致膀胱功能和结构发生显著变化，并最终可能对肾功能有害。病理性膀胱重塑的分子信号以及性别影响仍知之甚少。
研究BOO一天后的膀胱重塑情况，不同膀胱节段的重塑是否存在差异，以及性别是否会影响重塑。
将30只雄性和30只雌性C57BL/6NRj小鼠随机分为对照组、假手术组和BOO组，每组10只。在尿道近端进行24小时的完全尿道梗阻。通过苏木精-伊红（H&E）、三色染色和免疫组织化学染色观察组织学变化。将收获的膀胱分为上下节段进行分析。通过蛋白质印迹法和定量聚合酶链反应（qPCR）检测蛋白质和基因表达。
BOO后未观察到膀胱壁厚度有显著变化，而仅在雌性小鼠中发现BOO后膀胱质量增加。我们检测到雄性膀胱上节段中纤连蛋白（FN）和α-平滑肌肌动蛋白（α-SMA）上调。雌性BOO小鼠膀胱的两个节段中α-SMA表达均增加，但两个膀胱节段中FN均未观察到差异。在雄性和雌性膀胱中均检测到BOO诱导的转化生长因子-β（TGF-β）和Gremlin上调，而仅在雄性膀胱中检测到骨形态发生蛋白-7（BMP-7）下调。此外，BOO后雄性膀胱中SMAD2/3和SMAD1/5/9的磷酸化均增加，而雌性小鼠膀胱上节段中磷酸化SMAD2/3增加，下节段中磷酸化SMAD1/5/9增加。
我们的数据表明，一些特定蛋白质和生长因子被检测为组织的早期改变，可能导致纤维化。此外，雄性的反应往往比雌性更明显。然而，这些发现的原因和后果需要进一步研究。
