Research background: Effects of hypoxia-inducible factor inhibition in an animal model of partial bladder outlet obstruction
Posterior urethral valves are abnormal flaps of tissue that block the urethra. This birth defect affects as many as one in 5,000 live births and is the most common cause of lower urinary tract obstruction in infants and children.
The blockage that results from posterior urethral valves, called a partial bladder outlet obstruction, can cause urine to back up in the bladder and throughout the urinary tract. Although advanced surgical interventions can relieve the valve obstruction, patients experience pathological changes in the bladder, long-term problems with voiding and potential future kidney failure.
Previous studies have suggested that hypoxia plays an important role in the development of bladder dysfunction following partial bladder obstruction. Hypoxia triggers the activation of proteins called hypoxia-inducible factors that alter the expression of genes to respond to the low-oxygen conditions.
To explore the role of hypoxia-inducible factor pathways in bladder pathology after urethral obstruction, investigators in the Department of Pediatric Urology at Children's Hospital Colorado studied the effects of blocking hypoxia-inducible factors in an animal model of partial bladder outlet obstruction.
In 5,000 births affected by partial bladder outlet obstruction
Common cause of lower urinary tract obstruction in infants and children
Research methods: Analysis of bladder function in male mice
The researchers surgically introduced partial bladder outlet obstructions in male mice. Control mice had sham surgery with no introduced obstruction. The mice received a placebo or a hypoxia-inducible factor inhibitor drug, called 17-DMAG, starting on the day of the surgery. The researchers removed the mouse bladders at two, four and seven days after the surgery to study tissue and cellular changes. They analyzed bladder function using in vitro recordings of muscle contractility.
Research results: Effects of partial bladder outlet construction and treatment with 17-DMAG to inhibit hypoxia-inducible factor pathways
Partial bladder outlet obstruction had the following effects:
- Increased bladder and kidney mass with increased collagen deposition in the bladder wall, suggesting muscle proliferation and extracellular matrix remodeling (scarring)
- Increased levels of hypoxia-inducible factor proteins Hif-1alpha and Hif-2alpha
- Increased expression of five hypoxia-inducible factor target genes that regulate blood vessel formation, energy metabolism and scarring, which are all associated with pathological changes induced by partial bladder outlet obstruction
- Reduced contractility of bladder muscle in response to potassium chloride and electrical stimulation, suggesting alterations in nerve-dependent responses
Treatment with 17-DMAG to inhibit hypoxia-inducible factor pathways in mice with partial bladder outlet obstruction had the following effects:
- Prevented an increase in bladder and kidney mass, and reduced the increase in collagen deposition in the bladder wall
- Partially blocked an increase in hypoxia-inducible factor proteins Hif-1alpha and Hif-2alpha
- Blocked an increase in four of five hypoxia-inducible factor pathway target genes
- Preserved contractility of bladder muscle
Research conclusion: Role of hypoxia-inducible factor pathway inhibition in the development of new therapies for partial bladder outlet obstruction
The current study shows that signaling pathways induced by oxygen deprivation – hypoxia-inducible factor pathways – contribute to bladder changes and dysfunction following partial bladder outlet obstruction. Blocking hypoxia-inducible factor pathways in a mouse model prevented the pathological changes associated with obstruction and maintained bladder muscle contractility.
The investigators studied the effects of hypoxia-inducible factor inhibition during the earliest stages of partial bladder outlet obstruction. Further studies are needed to evaluate the effects of long-term hypoxia-inducible factor inhibition on the pathological changes resulting from partial bladder outlet obstruction.
The current study's findings suggest that hypoxia-inducible factor pathway inhibition may be a valuable target for developing therapeutics to improve urinary tract function in infants and children after surgical intervention to prevent the long-term effects. Hypoxia-inducible factor inhibitors are currently being tested in clinical trials for other conditions.
This study was published in the April 2016 issue of the Journal of Urology.