Bladder stromal loss of transforming growth factor receptor II decreases fibrosis after bladder obstruction.
OBJECTIVE
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.


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.
Anumanthan
Govindaraj
G
Department of Urologic Surgery, Division of Pediatric Urology, Vanderbilt Children's Hospital, Nashville, Tennessee 37232-2765, USA.
Tanaka
Stacy T
ST
Adams
Cyrus M
CM
Thomas
John C
JC
Wills
Marcia L
ML
Adams
Mark C
MC
Hayward
Simon W
SW
Matusik
Robert J
RJ
Bhowmick
Neil A
NA
Brock
John W
JW
Pope
John C
JC
D000818:Animals; D005260:Female; D005355:Fibrosis; D051379:Mice; D008810:Mice, Inbred C57BL; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism* / Q000502:physiology; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000502:physiology; D001743:Urinary Bladder / Q000378:metabolism* / Q000473:pathology*; D001748:Urinary Bladder Neck Obstruction / Q000473:pathology*
D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II
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