Potential beneficial effect of tocotrienols on lower urinary dysfunction associated with partial bladder outlet obstruction
Nao Iguchi, PhD1, M Irfan Donmez, MD2, Anna P. Malykhina, PhD1, Duncan T. Wilcox, MBBS, MD3.
1University of Colorado AMC, Aurora, CO, USA, 2Istanbul University, Istanbul, Turkey, 3Children's Hospital Colorado, Aurora, CO, USA.
Background: Bladder dysfunction due to posterior urethral valves is a major issue that contributes to renal impairment of those patients. Surgical procedures can improve lower urinary tract symptom in most of patients with PUV, however, the effect on the kidneys and the urinary bladder often persists even after the successful surgical management. Currently, the treatment options for bladder dysfunction due to PUV/PBOO are limited mostly to palliative measures, warranting demands for targeted therapies to reduce or prevent the bladder histopathological changes and support normal bladder growth and preserve renal function. Hypoxia inducible factor (HIF) pathway has been shown to be involved in bladder dysfunction caused by partial bladder outlet obstruction (PBOO). The objective of this study was to test our hypothesis that tocotrienols (minor ingredients of vitamin E) may have beneficial effects on bladder function following PBOO via inhibiting HIF pathways in a juvenile murine model.
METHODS: PBOO was surgically created by ligation of the bladder neck in 4-week-old C57BL/6 male mice. Sham operated mice served as control. Each group of animals received either soybean oil (SBO, vehicle) or tocotrienol (T3) enriched fraction by oral administration from 0 to 13 days post-surgery. Bladder function was examined in vivo by void spot assays at 1- and 2 weeks post-op. At 2 weeks post-surgery, the bladders were subjected to 1) physiological evaluation of detrusor contractility in vitro using bladder strips, 2) histology by H&E staining and collagen imaging, and 3) gene expression analyses by qPCR.
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+T3 group (Fig 1). PBOO-induced decrease in detrusor contractility was similar between the 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, Fig.2). 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.
Conclusions: Oral tocotrienol treatment reduced the progression of urinary frequency and bladder fibrosis at least partially through suppressing HIF pathways triggered by PBOO, and therefore may reduce the risk of related bladder dysfunction and renal insufficiency.
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