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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.