title: Chronic cyclic bladder over distention up-regulates hypoxia dependent pathways.
abstract: OBJECTIVE
  Bladder over distention secondary to anatomical or functional obstruction can eventually lead to pathological changes, including decreased elasticity and contractile dysfunction. We hypothesized that chronic bladder distention in a murine model would activate hypoxia dependent signaling pathways despite intermittent relief of distention.
  
  
  METHODS
  Female C57Bl/6 mice were oophorectomized at age 5 to 6 weeks and underwent urethral catheterization and 90-minute bladder distention. Acute and chronic time points were evaluated. Bladder tissue was harvested for hematoxylin and eosin, and immunohistochemical staining with the hypoxia markers Glut-1 (EMD Millipore, Merck, Darmstadt, Germany) and Hypoxyprobe™-1. Bladder tissue was also harvested for real-time polymerase chain reaction and oxidative stress measurement. Hypoxia polymerase chain reaction arrays were done to determine changes in gene expression. Oxidative stress was measured using F2-IsoP. Functional bladder changes were evaluated using voided urine blots.
  
  
  RESULTS
  After acute distention and 5 consecutive distentions, bladders showed marked inflammatory changes on hematoxylin and eosin staining, and evidence of tissue hypoxia on immunohistochemistry. Quantitative real-time polymerase chain reaction revealed up-regulation of hypoxia and oxidative stress related genes, including Hif1a, Arnt2, Ctgf, Gpx1 and Hmox1. Measurements of oxidative stress with F2-IsoP did not change. Voided urine blots before and after bladder distention showed marked changes with an overactive voiding pattern.
  
  
  CONCLUSIONS
  Chronic bladder distention is possible in the female mouse. It generates hypoxic injury, as characterized functionally by increased voiding patterns. This bladder injury model might more closely replicate bladder dysfunction in patients with poor bladder emptying due to neurological disease, including those noncompliant with intermittent catheterization.
authors: Division of Pediatric Urology, Monroe Carell Jr. Children's Hospital at Vanderbilt, Nashville, Tennessee.
authors: Heidi A
authors: HA
authors: Stephany
authors: Douglas W
authors: DW
authors: Strand
authors: Christina B
authors: CB
authors: Ching
authors: Stacy T
authors: ST
authors: Tanaka
authors: Ginger L
authors: GL
authors: Milne
authors: Mariana M
authors: MM
authors: Cajaiba
authors: John C
authors: JC
authors: Thomas
authors: John C
authors: JC
authors: Pope
authors: Mark C
authors: MC
authors: Adams
authors: John W
authors: JW
authors: Brock
authors: Simon W
authors: SW
authors: Hayward
authors: Robert J
authors: RJ
authors: Matusik
authors: Douglass B
authors: DB
authors: Clayton
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D051272:Glucose Transporter Type 1 / Q000096:biosynthesis / Q000235:genetics*; D000860:Hypoxia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress; D012313:RNA / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D015854:Up-Regulation; D001743:Urinary Bladder / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D001748:Urinary Bladder Neck Obstruction / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014554:Urination
chemical_list: D051272:Glucose Transporter Type 1; C495678:Slc2a1 protein, mouse; D012313:RNA
keywords: Arnt2; Ctgf; F2-IsoP; F2-isoprostane; Glut-1; Gpx1; HIF; Hmox1; ROS; anoxia; arylhydrocarbon receptor nuclear translocator 2; connective tissue growth factor; gene expression; glucose transporter 1; glutathione peroxidase 1; hemoxygenase 1; hypoxia-inducible factor; oxidative stress; pBOO; partial bladder outlet obstruction; qRT-PCR; quantitative real-time polymerase chain reaction; reactive oxygen species; urinary bladder; urinary bladder neck obstruction