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16:11 - 16:14
S2-13
(PP)
ROLE OF DNA-METHYLATION IN PARTIAL BLADDER OUTLET OBSTRUCTION
Martin SIDLER
1
, Karen AITKEN
2
, Jia-Xin JIANG
2
, Alaleh SAMIEI
2
and Darius BAGLI
3
1) University of Toronto, Institute of Medical Sciences, Toronto, CANADA - 2) Research Institute, Sickkids Hospital,
Developmental and Stem Cell Biology, Toronto, CANADA - 3) Sickkids Hospital, Division of Urology, Department of
Surgery, Toronto, CANADA
PURPOSE
Partial bladder outlet obstruction (PBO), occurring in diseases such as prostate hyperplasia, is a widespread cause of
urinary dysfunction. Bladder remodelling due to PBO follows a sequence of overlapping processes of inflammation,
hypertrophy and hyperplasia and bladder fibrosis. Epigenetic changes such as DNA methylation play an important role in
adaptive processes. In order to evaluate its role in bladder remodelling, we used a hypomethylating agent in a rodent
model during the adaptive phase of PBO.
MATERIAL AND METHODS
20 Sprague-Dawley female rats underwent PBO by tying a silk suture around the proximal urethra and a 0.9mm steel
rod, which was then removed. Sham operation without the suture was done in 12 rats. After 2 weeks, rats were
randomized to normal saline (NS) or treatment with the DNA methyltransferase inhibitor, 5-aza-2′-deoxycytidine (DAC),
at 1mg/kg, 3 times/week intraperitoneally. We recorded sleep micturition patterns at 6 weeks post-obstruction to
analyse micturition volumes, frequencies and bladder capacities. We measured residual volumes in anaesthetized rats,
which were sacrificed to measure bladder and body weights. Histologic workup and high-throughput qPCR (HTQPCR) of
candidate genes were performed.
RESULTS
In the obstructed rats, DAC treatment significantly increased micturition frequency 2-fold and significantly decreased
mean micturition volume vs. controls (p<0.05). While DAC plus PBO significantly increased maximal bladder capacity
and residual volume vs. PBO alone, DAC treatment in sham-operated rats had no effect on these parameters. Bladder
weight was significantly increased in DAC obstructions vs obstruction alone, while treatment caused no difference in the
sham-operated groups. HT-QPCR and histology indicated that DAC released control of expression of the neurotrophic
BDNF and adrenergic receptor 1 and collagen-inducing CTGF.
CONCLUSIONS
Pharmacological inhibition of DNA methylation is crucial factor for regulating the neurotrophic and ecm regulating genes
in PBO, in concordance with changes in function.