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PREVENTION OF BLADDER DYSFUNCTION BY THE POTENT HYPOXIA INDUCIBLE
FACTOR INHIBITOR, 17-DMAG, IN A MOUSE MODEL OF PARTIAL BLADDER
OBSTRUCTION
Nao IGUCHI
1
, Anna MALYKHINA
1
and Duncan WILCOX
2
1) University of Colorado Denver, School of Medicine, Surgery/Urology, Aurora, USA - 2) Children's Hospital Colorado,
Aurora, USA
PURPOSE
Posterior urethral valves are the commonest cause of partial bladder outlet obstruction (PBOO) in the pediatric
population, resulting in significant morbidity and mortality. Recent studies suggest that the etiology of pathological
changes induced by PBOO is partly due to hypoxia induced by ischemia, which mediates the activity of the Hypoxia
Inducible Factors (HIFs). HIFs regulate gene expression in angiogenesis, cell proliferation, and fibrosis. Our hypothesis
was that 17-DMAG, a potent HIF blocker would partially reverse the pathophysiological changes in PBOO mouse model.
MATERIAL AND METHODS
PBOO was created in male mice (6-8 weeks) by tying 1Fr tubing externally alongside the proximal urethra with 4−0 silk,
followed by the removal of the tube. Sham animals served as controls underwent the same procedure without urethral
ligation. Animals were treated either with 17−DMAG or placebo daily up to 5 days starting from the day of surgery.
Bladders were harvested at 7 days post−surgery, and subjected to pathophysiological evaluation.
RESULTS
Immunohistochemical analysis showed that 17−DMAG treatment prevented an up−regulation of HIF proteins and
collagen III in the obstructed bladders. Detrusor muscle strips from PBOO mice developed reduced contractile force in
response to electric field stimulation and KCl in comparison with sham controls (N ≥3 each group). The 17−DMAG
treatment improved muscle contractility to both stimuli (68-74% vs. 34-40%, Sham as 100%) in PBOO mice.
CONCLUSIONS
The results of this study suggest that the blockade of HIF pathways may preserve detrusor muscle function in PBOO
mice. Inhibition of HIF pathway has a potential clinical implication for the development of novel pharmacological
therapies to treat PBOO−associated pathology.