Chronic cyclic bladder over distention up-regulates hypoxia dependent pathways

Heidi A. Stephany, Douglas W. Strand, Christina B. Ching, Stacy T. Tanaka, Ginger L. Milne, Mariana M. Cajaiba, John C. Thomas, John C. Pope IV, Mark C. Adams, John W. Brock, Simon W. Hayward, Robert J. Matusik, Douglass B. Clayton

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

Purpose 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. Materials and 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.

Original languageEnglish (US)
Pages (from-to)1603-1609
Number of pages7
JournalJournal of Urology
Volume190
Issue number4 SUPPL
DOIs
StatePublished - Oct 2013

Keywords

  • oxidative stress anoxia gene expression urinary bladder neck obstruction
  • urinary bladder

ASJC Scopus subject areas

  • Urology

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    Stephany, H. A., Strand, D. W., Ching, C. B., Tanaka, S. T., Milne, G. L., Cajaiba, M. M., Thomas, J. C., Pope IV, J. C., Adams, M. C., Brock, J. W., Hayward, S. W., Matusik, R. J., & Clayton, D. B. (2013). Chronic cyclic bladder over distention up-regulates hypoxia dependent pathways. Journal of Urology, 190(4 SUPPL), 1603-1609. https://doi.org/10.1016/j.juro.2013.02.026