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Study for the Effects of Blocking Hypoxia Inducible Factors in the Pathogenesis Following Partial Bladder Outlet Obstruction
Nao Iguchi, PhD1, Duncan T. Wilcox, MD2.
1University of Colorado Anschutz Medical Campus, Aurora, CO, USA, 2Children's Hospital Colorado, Aurora, CO, USA.

BACKGROUND: Posterior urethral valves (PUV) are the commonest cause of bladder outlet obstruction (BOO) in the pediatric population. PUV is a devastating clinical problem that can result in urinary incontinence, neurogenic bladder and renal impairment. Previous studies have suggested that hypoxia and the resulting activation of the transcriptional factors; hypoxia-inducible factors (HIFs) play a role in pathological changes secondary to BOO. The HIF pathway can be blocked using 17-Dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG). We hypothesized that BOO causes bladder muscle changes, mediated via hypoxia and the HIF pathway, which could be alleviated by blocking the pathway.
METHODS: After obtaining IRB approval from our institution, male mice underwent surgical obstruction or a sham operation, with sham animals serving as controls. Partial BOO was created by isolating the prostatic urethra and tying 1Fr polyethylene tubing externally alongside the urethra, with 4−0 silk, and then removing the tube. All mice received carprofen for postoperative pain control. Animals with partial BOO were divided into 2 groups, Group T and P. Mice received either 15mg/kg of a testing agent, (17-DMAG) [Group T] or water [Group P] orally at 0 and every 24 hrs post-surgery. Bladders and kidneys were harvested from mice from each group at 4 days post surgery and subjected to histological and molecular biological analyses by using RT−PCR and immunohistochemistry.
RESULTS: The bladder mass in the Group P animals were significantly increased compared to those in the Group T mice (0.15 ± 0.01 vs. 0.09 ± 0.00 % of body weight). There was no difference in the bladder mass between the Group T and sham-operated mice (0.10 ± 0.01 % of body weight). PBOO induced the upregulation of HIFs, genes which are believed to be regulated by HIFs including Glut-1, and Twist, and inflammation markers, such as IL-1β and IL-8. We detected the trend of the elevation of those genes in the bladders from the Group P mice, but not in those from the Group T mice.
CONCLUSIONS: The treatment with 17-DMAG resulted in the alleviation of the BOO-induced increase in bladder weight and expression level of HIF-target genes and inflammation markers in BOO mouse model. These results suggest that hypoxia-HIFs pathway is involved in the development of pathological changes following BOO.

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