Increased rates of vesicoureteral reflux in mice from deletion of Dicer in the peri-Wolffian duct stroma

Abstract

BACKGROUND: Vesicoureteral reflux (VUR), backflow of urine into the kidney, is associated with urinary tract infections and chronic kidney disease. Integrity of the vesicoureteral junction (VUJ), where reflux occurs, is determined largely by proper induction of the ureteric bud from the Wolffian duct. Induction is modulated by signals from the surrounding peri-Wolffian duct stroma. We evaluated whether miRNAs in the peri-Wolffian duct stroma are necessary for proper ureteric induction, VUJ formation, and suppression of VUR. METHODS: We generated a mouse with loss of miRNAs in the peri-Wolffian duct stroma. We evaluated embryos for ureteric bud induction defects and expression of genes that regulate induction. We performed cystograms to assess for reflux and assessed VUJs in postnatal mice. RESULTS: Mutant embryos had cranially displaced ureteric bud induction sites versus controls. We observed no changes in expression of genes known to regulate induction. While mutants were early postnatal lethal, they had high rates of VUR versus controls. Mutant VUJs that refluxed had low inserting ureters and shortened intravesicular tunnels versus non-refluxing mice. CONCLUSIONS: We found that miRNAs in the peri-Wolffian duct stroma are required for normal ureteric bud induction, VUJ formation, and prevention of VUR.

X-ray videocystometry for high-speed monitoring of urinary tract function in mice

“…on August 1, 2021 http://advances.sciencemag.org/ Downloaded from important risk factor for pyelonephritis and chronic kidney disease. Although there are several mouse models of VUR (21)(22)(23)(24), assays to study the pathophysiology of VUR are limited. The current gold-standard assay, the euthanized cystogram, involves the pressure injection of dye in the bladder of euthanized animals, preventing the repetitive assessment of VUR during normal physiological bladder function (20,21).…”

“…The current standard method to evaluate VUR in mice entails the qualitative assessment of pressure-induced flux of dye from the bladder to the kidneys in euthanized animals (euthanized cystogram) (20,21). Whereas this approach has allowed detecting variable degrees of VUR in several inbred and genetically modified mice (21)(22)(23)(24), it does not allow assessment of VUR during normal bladder filling/voiding cycles, and death may affect the parameters that determine reflux.…”