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

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.

PBOO was surgically created in juvenile male mice. Sham-operated mice were used as controls. Animals received daily oral administration of either tocotrienols (T₃) 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.

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+T₃ group. PBOO-induced decrease in detrusor contractility was similar between two treatments. PBOO induced bladder hypertrophy to the same degree in both SBO and T₃ treatment groups, however, fibrosis in the bladder was significantly less prominent in the T₃ 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+T₃ group compared to the control.

Oral tocotrienol treatment reduced the progression of urinary frequency and bladder fibrosis by suppressing HIF pathways triggered by PBOO.