Anti-fibrotic effect of tocotrienols for bladder dysfunction due to partial bladder outlet obstruction

PURPOSE: To investigate potential beneficial effects of tocotrienols which have been suggested to inhibit hypoxia-inducible factor (HIF) pathway, on partial bladder outlet obstruction (PBOO)-induced bladder pathology. MATERIALS AND METHODS: PBOO was surgically created in juvenile male mice. Sham-operated mice were used as controls. Animals received daily oral administration of either tocotrienols (T(3)) or soybean oil (SBO, vehicle) from day 0 to 13 post-surgery. Bladder function was examined in vivo by void spot assay. At 2 weeks post-surgery, the bladders were subjected to physiological evaluation of detrusor contractility in vitro using bladder strips, histology by H&E staining and collagen imaging, and gene expression analyses by quantitative PCR. RESULTS: A significant increase in the number of small voids was observed after 1 week of PBOO compared to the control groups. At 2 weeks post-surgery, PBOO+SBO mice showed a further increase in the number of small voids, which was not observed in PBOO+T(3) group. PBOO-induced decrease in detrusor contractility was similar between two treatments. PBOO induced bladder hypertrophy to the same degree in both SBO and T(3) treatment groups, however, fibrosis in the bladder was significantly less prominent in the T(3) group than the SBO group following PBOO (1.8- vs. 3.0-fold increase in collagen content compared to the control). Enhanced levels of HIF target genes in the bladders were observed in PBOO+SBO group, but not in PBOO+T(3) group compared to the control. CONCLUSIONS: Oral tocotrienol treatment reduced the progression of urinary frequency and bladder fibrosis by suppressing HIF pathways triggered by PBOO.