Anumanthan Govindaraj, Tanaka Stacy T, Adams Cyrus M, Thomas John C, Wills Marcia L, Adams Mark C, Hayward Simon W, Matusik Robert J, Bhowmick Neil A, Brock John W, Pope John C
Department of Urologic Surgery, Division of Pediatric Urology, Vanderbilt Children's Hospital, Nashville, Tennessee 37232-2765, USA.
J Urol. 2009 Oct;182(4 Suppl):1775-80. doi: 10.1016/j.juro.2009.05.126. Epub 2009 Aug 18.
Transforming growth factor-beta is a potent stimulator of extracellular matrix production. Several studies show that loss of transforming growth factor-beta signaling decreases kidney, liver and lung fibrosis. However, the role of transforming growth factor-beta signaling in bladder fibrosis is not entirely understood. We investigated the effect of stromal loss of such signaling in mice after partial bladder outlet obstruction.
We performed partial bladder outlet obstruction by urethral ligation in 5-week-old female Tgfbr2(colTKO) mice. These mice were compared to WT mice with partial bladder outlet obstruction and to WT nonobstructed controls. After 4 weeks and before sacrifice urodynamics were performed. Bladder tissue was harvested, and p-Smad2 and collagen (Masson's trichrome) staining were performed.
Bladder compliance was increased in partially obstructed Tgfbr2(colTKO) mice and decreased in partially obstructed WT mice. The latter had increased smooth muscle hypertrophy and increased collagen deposition between smooth muscle bundles compared to those in Tgfbr2(colTKO) mice and nonobstructed controls. Transforming growth factor-beta responsive collagen promoter activity was significantly decreased in Tgfbr2 knockout bladder stromal cells vs WT stromal cells.
Stromal loss of transforming growth factor-beta signaling decreased collagen deposition after partial bladder outlet obstruction. In contrast to collagen production by recruited macrophages, stromal transforming growth factor-beta signaling appears to be the primary source of fibrosis after partial bladder outlet obstruction. These findings further support the hypothesis that manipulating transforming growth factor-beta signaling in bladder stromal cells would provide a future avenue for neuropathic bladder and bladder fibrosis treatment.
转化生长因子-β是细胞外基质产生的强效刺激因子。多项研究表明，转化生长因子-β信号通路的缺失可减轻肾脏、肝脏和肺部的纤维化。然而，转化生长因子-β信号通路在膀胱纤维化中的作用尚未完全明确。我们研究了部分膀胱出口梗阻后小鼠基质中该信号通路缺失的影响。
我们通过尿道结扎对5周龄雌性Tgfbr2（colTKO）小鼠进行部分膀胱出口梗阻。将这些小鼠与部分膀胱出口梗阻的野生型小鼠以及未梗阻的野生型对照小鼠进行比较。在4周后处死前进行尿动力学检查。收集膀胱组织，进行p-Smad2和胶原蛋白（Masson三色染色）染色。
部分梗阻的Tgfbr2（colTKO）小鼠膀胱顺应性增加，而部分梗阻的野生型小鼠膀胱顺应性降低。与Tgfbr2（colTKO）小鼠和未梗阻的对照小鼠相比，后者平滑肌肥大增加，平滑肌束间胶原蛋白沉积增加。与野生型基质细胞相比，Tgfbr2基因敲除的膀胱基质细胞中转化生长因子-β反应性胶原蛋白启动子活性显著降低。
部分膀胱出口梗阻后，转化生长因子-β信号通路的基质缺失减少了胶原蛋白沉积。与募集的巨噬细胞产生胶原蛋白不同，基质转化生长因子-β信号通路似乎是部分膀胱出口梗阻后纤维化的主要来源。这些发现进一步支持了这样的假设，即操纵膀胱基质细胞中的转化生长因子-β信号通路将为神经源性膀胱和膀胱纤维化的治疗提供一条未来途径。
