Vesicoureteral reflux (VUR- backflow of urine from the bladder into the ureter) is the most common urogenital anomaly in children and reflux nephropathy is the 4th leading cause of chronic renal failure in children. The application's broad long-term objectives are to understand the pathophysiology of vesicoureteral reflux and reflux nephropathy in children to ultimately offer the most appropriate treatment strategies. To that end, a mouse line has been generated that is a novel genetic model of vesicoureteral reflux. The mice, designated fgfr2Mes-/- (due to conditional deletion of fibroblast growth factor receptor 2 from kidney metanephric mesenchyme), frequently have abnormalities in ureteric bud induction site(s), which likely leads to the high incidence of VUR in young post natal mice. Many adult fgfr2Mes-/- mice with persistent VUR (but no obvious urinary tract infections) have scarring, consistent with reflux nephropathy. These same mice have evidence of myofibroblast transformation consistent with transforming growth factor beta (TGF-2) mediated injury. It is our working hypothesis that the fgfr2Mes-/- mice represent a unique genetic model of vesicoureteral reflux and sterile reflux nephropathy, and that TGF-2 signaling is a key molecular pathway mediating renal injury in reflux nephropathy. To test this hypothesis, the following aims have been generated:
Specific Aim 1 : Elucidate why the fgfr2Mes-/- mice are prone to VUR, examining formation of the ureter, bladder and ureter-bladder (ureterovesicle) junction.
Specific Aim 2 : Completely characterize the natural history of VUR and reflux nephropathy in fgfr2Mes-/- mice.
Specific Aim 3 : Elucidate the role of aberrant TGF-2 signaling in the progression of reflux nephropathy, including its utility as a therapeutic target. This unique mouse model will permit careful evaluation of the pathophysiology of vesicoureteral reflux and reflux nephropathy, which should provide novel therapeutic strategies for children with these conditions.

Public Health Relevance

Vesicoureteral reflux (backflow of urine from the bladder into the ureter toward the kidney) is the most common urinary tract birth defect. This often leads to reflux nephropathy, a leading cause of kidney failure in children. We have a mouse mutant that develops reflux and subsequent reflux nephropathy. This mouse model will help us determine how best to treat children with this condition.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZRG1-RUS-B (04))
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Hoshizaki, Deborah K
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University of Pittsburgh
Schools of Medicine
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Walker, Kenneth A; Sims-Lucas, Sunder; Di Giovanni, Valeria E et al. (2013) Deletion of fibroblast growth factor receptor 2 from the peri-wolffian duct stroma leads to ureteric induction abnormalities and vesicoureteral reflux. PLoS One 8:e56062
Carpenter, Ashley; Paulus, Andrew; Robinson, Melissa et al. (2012) 3-Dimensional morphometric analysis of murine bladder development and dysmorphogenesis. Dev Dyn 241:522-33
Paredes, Jose; Sims-Lucas, Sunder; Wang, Hang et al. (2011) Assessing vesicoureteral reflux in live inbred mice via ultrasound with a microbubble contrast agent. Am J Physiol Renal Physiol 300:F1262-5
Bates, Carlton M (2011) Role of fibroblast growth factor receptor signaling in kidney development. Pediatr Nephrol 26:1373-9
Bates, Carlton M (2011) Role of fibroblast growth factor receptor signaling in kidney development. Am J Physiol Renal Physiol 301:F245-51
Hains, David S; Sims-Lucas, Sunder; Carpenter, Ashley et al. (2010) High incidence of vesicoureteral reflux in mice with Fgfr2 deletion in kidney mesenchyma. J Urol 183:2077-84