title: A Role for the Hedgehog Effector Gli1 in Mediating Stent-induced Ureteral Smooth Muscle Dysfunction and Aperistalsis.
abstract: OBJECTIVE
  To better understand the effects of double J stenting on ureteral physiology and function.
  
  
  METHODS
  In total, 24 pigs were stented cystoscopically unilaterally for 48 hours, 1, 2, 4, and 7 weeks. Controls consisted of un-stented animals (n = 4) or the contralateral un-stented ureter in pigs. Ureters were harvested and tested in tissue baths to evaluate their contractility. Ureteral inflammation and expression of Sonic Hedgehog (Shh) and the transcriptional activator Gli1 (the downstream target of active Hedgehog signaling) were assessed histologically and by immunohistochemistry, respectively.
  
  
  RESULTS
  Indwelling ureteral stents were found to abolish normal ureteral function in all animals. Specifically, ureteral smooth muscle (SM) activity was significantly diminished within 48 hours after stenting and persisted at the 1-week time point. Furthermore, ureteral SM dysfunction was associated with increasing ureteral dilation due to the indwelling stent. Simultaneously, we observed a loss of Gli1 expression in SM cells, with a concomitant increase in ureteral inflammation. Expression of Shh was restricted to the urothelium and was not different between controls, stented, and contralateral ureters.
  
  
  CONCLUSIONS
  Stent-induced aperistalsis was associated with diminished SM contractility, increased tissue inflammation, and reduced Gli1 expression in ureteral SM cells, independent of Shh expression. The present study is the first to show that indwelling stents negatively affect ureteral SM activity and identify a role for specific molecular mechanisms involved.
authors.affiliation: Department of Urologic Sciences, The Stone Centre at Vancouver General Hospital, University of British Columbia, Vancouver, BC, Canada; Department of Urology, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Janssen
authors.affiliation: Department of Urologic Sciences, Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Ralph
authors.initials: R
authors.lastname: Buttyan
authors.affiliation: Department of Pathology and Laboratory Medicine, James Hogg Research Centre, St. Paul Hospital/Providence Health Care, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Chun Y
authors.initials: CY
authors.lastname: Seow
authors.affiliation: Department of Urology, Johannes Gutenberg University, Mainz, Germany; Department of Urologic Sciences, Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Jäger
authors.affiliation: Department of Pathology and Laboratory Medicine, James Hogg Research Centre, St. Paul Hospital/Providence Health Care, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Dennis
authors.initials: D
authors.lastname: Solomon
authors.affiliation: Department of Urologic Sciences, Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Ladan
authors.initials: L
authors.lastname: Fazli
authors.affiliation: Department of Urologic Sciences, The Stone Centre at Vancouver General Hospital, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Ben H
authors.initials: BH
authors.lastname: Chew
authors.affiliation: Department of Urologic Sciences, The Stone Centre at Vancouver General Hospital, University of British Columbia, Vancouver, BC, Canada. Electronic address: dlange@mail.ubc.ca.
authors.forename: Dirk
authors.initials: D
authors.lastname: Lange
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation; D007249:Inflammation; D009130:Muscle, Smooth / Q000378:metabolism*; D010528:Peristalsis; D015398:Signal Transduction; D015607:Stents; D013552:Swine; D013997:Time Factors; D014513:Ureter / Q000378:metabolism*; D014517:Ureteral Obstruction / Q000473:pathology; D000071676:Zinc Finger Protein GLI1 / Q000378:metabolism*
chemical_list: D000071676:Zinc Finger Protein GLI1