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INHIBITION OF DNA-METHYLATION ENHANCES FUNCTIONAL RECOVERY AFTER
RELEASE OF BLADDER OUTLET OBSTRUCTION.
Martin SIDLER
1
, Karen AITKEN
2
, Janet JIANG
2
, Alaleh SAMIEI
2
and Darius BAGLI
2
1) University of Toronto and Sickkids Research Institute, Institute of Medical Sciences, Toronto, CANADA - 2) Research
Institute, Sickkids Hospital, Developmental and Stem Cell Biology, Toronto, CANADA
PURPOSE
Long-term partial bladder outlet obstruction (PBO), in diseases such as prostate hyperplasia or posterior urethral valves,
is a widespread cause of urinary dysfunction. Bladder remodelling due to PBO involves overlapping processes of
inflammation, hypertrophy and hyperplasia leading to irreversible fibrosis. Epigenetic changes, such as DNA
methylation, contribute persistent fibrosis and dysfunction in other diseases. We hypothesized that inhibition of DNA
methylation enhances recovery after release of obstruction.
MATERIAL AND METHODS
24 Sprague-Dawley female rats underwent PBO by tying a silk suture around the proximal urethra and 0.9mm steel rod;
the latter was then removed. Sham operation without tying the suture was done in 12 rats. 6 weeks later, we recorded
sleep micturition patterns. We then removed the suture in PBO rats or exposed the proximal urethra in sham-operated
animals. Animals in each group were randomized to treatment with normal saline (NS) or DNA methyltransferase
inhibitor, 5-aza-2′-deoxycytidine (DAC), at 1mg/kg 3-times/week intraperitoneally for 4 weeks. The DAC dose had
proven hypomethylating activity. 4 weeks after the secondary procedure, we recorded micturition patterns again to
analyze micturition volumes, frequencies and bladder capacities. We determined residual volumes in anaesthetized rats,
followed by sacrificed to measure bladder and body weights and harvest bladder tissue for future histologic workup,
qPCR and evaluation of gene-specific methylation levels.
RESULTS
In the obstructed and later deobstructed rats, residual volumes of the DAC treated group were not significantly higher
than in the NS group. Among the same animals, DAC treatment helped preserve micturition volume (data shows a
trend) with a significant (p=0.05) increase in micturition fraction (ratio “mean voided volume”/”maximum bladder
capacity”) by one third.
CONCLUSIONS
In bladders, persistently altered by PBO, inhibition of DNA-methylation enhances functional recovery AFTER release of
obstruction. Further analysis is necessary to characterize the underlying mechanisms.