title: Rapamycin attenuates bladder hypertrophy during long-term outlet obstruction in vivo: tissue, matrix and mechanistic insights.
abstract: OBJECTIVE
  Previous molecular studies showed that the mTOR inhibitor rapamycin prevents bladder smooth muscle hypertrophy in vitro. We investigated the effect of rapamycin treatment in vivo on bladder smooth muscle hypertrophy in a rat model of partial bladder outlet obstruction.
  
  
  METHODS
  A total of 48 female Sprague-Dawley® rats underwent partial bladder outlet obstruction and received daily subcutaneous injections of rapamycin (1 mg/kg) or vehicle commencing 2 weeks postoperatively. A total of 36 rats underwent sham surgery and received rapamycin or vehicle. Rats were sacrificed 3, 6 and 12 weeks after surgery. Before sacrifice, voiding was observed in a metabolic cage for 24 hours. Bladder-to-body weight in gm bladder weight per kg body weight and post-void residual urine were assessed. We evaluated Col1a1, Col3a1, Eln and Mmp7 mRNA expression and histology. Two-factor ANOVA and the post hoc t test were applied.
  
  
  RESULTS
  Bladder outlet obstruction caused a significant increase in bladder weight in all obstructed groups. Three weeks postoperatively (1 week of treatment) there was no difference in the bladder-to-body weight ratio in the obstructed group. However, at 6 and 12 weeks (4 and 10 weeks of treatment, respectively) the bladder-to-body weight ratio of rats with obstruction plus rapamycin was significantly lower than that of rats with obstruction plus vehicle. Post-void residual urine volume after 6 and 12 weeks of obstruction was lower in obstructed rats with rapamycin compared to that in obstructed rats with vehicle. Rapamycin decreased the obstruction induced expression of Col1a1, Col3a1, Eln and Mmp7.
  
  
  CONCLUSIONS
  Rapamycin prevents mechanically induced hypertrophy in cardiovascular smooth muscle. In vivo mTOR inhibition may attenuate obstruction induced detrusor hypertrophy and help preserve bladder function.
authors: Department of Urology, Hospital for Sick Children, Ontario, Canada.
authors: Annette
authors: A
authors: Schröder
authors: Tyler P
authors: TP
authors: Kirwan
authors: Jia-Xin
authors: JX
authors: Jiang
authors: Karen J
authors: KJ
authors: Aitken
authors: Darius J
authors: DJ
authors: Bägli
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001707:Biopsy, Needle; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006984:Hypertrophy / Q000188:drug therapy / Q000473:pathology; D007150:Immunohistochemistry; D007279:Injections, Subcutaneous; D009122:Muscle Hypertonia / Q000188:drug therapy / Q000473:pathology; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome; D001743:Urinary Bladder / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D001748:Urinary Bladder Neck Obstruction / Q000188:drug therapy* / Q000473:pathology*
chemical_list: C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus