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Urologic Diseases Research Updates
Mouse Model Sheds Light on VUR
Common Urinary Tract Defect in Children
A new strain of mice is helping scientists understand a birth defect that affects thousands of children every year. Vesicoureteral reflux (VUR)—the backward flow of urine from the bladder into the ureters and kidneys—is the most common urinary birth defect in children. In VUR, the valve that normally stops urine from reentering the ureter does not work properly. VUR can lead to urinary tract infections and scarring in the kidneys. In the worst cases, VUR can result in reflux nephropathy, a leading cause of kidney failure in children.
Researchers have noted that VUR tends to run in families, but the genetic causes of VUR are not fully understood. To learn more about the genes involved in VUR, Carlton Matthew Bates, M.D., University of Pittsburgh, and his colleagues, with a grant from the National Institute of Diabetes and Digestive and Kidney Diseases, have developed a strain of mice with hereditary VUR. This mouse model is helping Dr. Bates and colleagues study the fetal development of the urinary tract.
During fetal development, the ureter begins as a ureteric bud that interacts with a layer of cells called the metanephric mesenchyme, which later develops into the kidney. Dr. Bates and colleagues have generated mice lacking a protein called fibroblast growth factor receptor 2 (Fgfr2) in the metanephric mesenchyme that have high rates of VUR. The mouse strain has therefore been named Fgfr2Mes-/-.
Dr. Bates and colleagues theorize that Fgfr2 plays a role in the normal development of the ureter and the ureterovesicle junction. Conversely, the lack of Fgfr2 can lead to abnormal development. In his grant application, Dr. Bates wrote, “The mice designated Fgfr2Mes-/- frequently have abnormalities in ureteric bud induction sites, which likely leads to the high incidence of VUR in young, post-natal mice.”
Dr. Bates and colleagues generated a different mouse line with mutations in both Fgfr1 and Fgfr2 that also lead to even more severely abnormal ureteric development in an article in the April 2012 issue of the Journal of the American Society of Nephrology. They conclude that ureteric morphogenesis requires both Fgfr1 and Fgfr2 signaling in the metanephric mesenchyme.
Understanding the mechanisms that foster normal ureteric development and the genetic mutations that interfere with that development will someday have bedside implications. Dr. Bates concludes, “We have mouse mutants that develop reflux and subsequent reflux nephropathy. These mouse models will help us determine how best to treat children with this condition.”
Learn more about urine reflux at www.kidney.niddk.nih.gov/KUDiseases/pubs/vesicoureteralreflux.
NIH Publication No. 13–5743
Page last updated January 31, 2013