Abstract: SA-OR049

Loss of Dicer Activity in the Peri-Wolffian Duct Stroma Leads to Increased Rates of Vesicoureteral Reflux

Session Information

Category: Developmental Biology and Inherited Kidney Diseases

  • 403 Pediatric Nephrology

Authors

  • Anslow, Melissa J., Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania, United States
  • Ho, Jacqueline, Children's Hosp of Pittsburgh of UPMC, Pittsburgh, Pennsylvania, United States
  • Bates, Carlton M., Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • Bodnar, Andrew J., Children's Hosp of Pittsburgh of UPMC, Pittsburgh, Pennsylvania, United States
  • Sims-Lucas, Sunder, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, United States
Background

Vesicoureteral reflux (VUR) is associated with urinary tract infections, hypertension, and reflux nephropathy, which is the 4th most frequent cause of end-stage renal disease in children. The formation of the vesicoureteral junction occurs during development through induction of the ureteric bud from the Wolffian duct, which requires signaling factors from both the Wolffian duct and surrounding stroma. VUR is known to be heritable, but very little is known about which specific genes are involved. miRNAs are small, noncoding RNAs that regulate gene expression post-transcriptionally. We hypothesize that miRNAs are also important in vesicoureteral junction development and play a role in VUR.

Methods

We generated a transgenic mouse model with loss of Dicer in the peri-Wolffian duct stroma. Dicer is a key component in the production of mature, functional miRNAs. Euthanized cystograms and 3D reconstructions of the ureters and bladder were performed on mutants (Tbx18Cre+:Dicerflx/flx) and controls (Tbx18Cre negative littermates).

Results

Euthanized cystograms demonstrated significantly higher rates of VUR in the mutant mice compared to control, ~42% (5/12) of Dicer mutants as opposed to ~5% (2/37) of controls (p < 0.01). Of the mutant mice, two had bilateral VUR and three had unilateral VUR. Preliminary 3D reconstruction data suggests lower ureteral insertion into the bladder in mutants compared to control mice.

Conclusion

Together, these data suggest for the first time that miRNAs play a role in VUR, and that this may be due to lower ureteral insertion into the bladder in mutant mice. Future work will further assess for ureteric bud induction abnormalities and explore other potential etiologies of increased VUR in the mutant mice.

Funding

  • NIDDK Support