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Evaluation of Biomaterials for Bladder Augmentation using Cystometric Analyses in Various Rodent Models
Published on: August 9, 2012
Bladder stromal loss of transforming growth factor receptor II decreases fibrosis after bladder obstruction
Govindaraj Anumanthan1, Stacy T Tanaka, Cyrus M Adams
1Department of Urologic Surgery, Division of Pediatric Urology, Vanderbilt Children's Hospital, Nashville, Tennessee 37232-2765, USA.
Purpose:
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.
Materials And Methods:
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.
Results:
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.
Conclusions:
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.
Insights
Stromal loss of transforming growth factor-beta signaling reduces bladder fibrosis after outlet obstruction. This suggests targeting stromal transforming growth factor-beta is a potential treatment for bladder fibrosis.
Area of Science:
- Urology
- Fibrosis Research
- Cell Signaling
Background:
- Transforming growth factor-beta (TGF-β) is a key regulator of extracellular matrix production.
- While TGF-β signaling's role in kidney, liver, and lung fibrosis is established, its impact on bladder fibrosis remains unclear.
- Investigating TGF-β signaling in bladder stromal cells is crucial for understanding bladder fibrosis.
Purpose of the Study:
- To investigate the role of stromal transforming growth factor-beta signaling in bladder fibrosis.
- To determine the effect of stromal loss of TGF-β signaling on bladder tissue after partial bladder outlet obstruction (PBOO).
Main Methods:
- Partial bladder outlet obstruction (PBOO) was induced in Tgfbr2(colTKO) mice (lacking TGF-β receptor 2 in stromal cells) and compared to wild-type (WT) mice.
- Urodynamics were performed, followed by bladder tissue harvesting for p-Smad2 and collagen (Masson's trichrome) staining.
- TGF-β responsive collagen promoter activity was assessed in WT and Tgfbr2 knockout bladder stromal cells.
Main Results:
- Partially obstructed Tgfbr2(colTKO) mice exhibited increased bladder compliance, unlike WT mice which showed decreased compliance.
- WT mice with PBOO displayed increased smooth muscle hypertrophy and collagen deposition compared to Tgfbr2(colTKO) mice.
- Collagen promoter activity was significantly lower in Tgfbr2 knockout bladder stromal cells than in WT stromal cells.
Conclusions:
- Loss of stromal TGF-β signaling significantly reduced collagen deposition following PBOO.
- Stromal TGF-β signaling, not collagen from macrophages, is the primary driver of fibrosis after PBOO.
- Targeting TGF-β signaling in bladder stromal cells may offer a therapeutic strategy for neuropathic bladder and bladder fibrosis.
