Basic Science Update: New Findings in Vesicoureteral Reflux

October 16, 2020

UPMC Children’s Hospital of Pittsburgh Division of Pediatric Nephrology researcher Melissa J. Anslow, MD, published new findings this year in the journal Pediatric Research on her research into the mechanisms and pathways of vesicoureteral reflux (VUR).

Dr. Anslow’s basic science laboratory is focused on congenital anomalies of the kidney and urinary tract. In 2018, Dr. Anslow was awarded a two-year K-12 institutional career development grant to pursue her research into how microRNAs (miRNAs) contribute to increased rates of VUR. Dr. Anslow has created a transgenic mouse model with a knockout of the Dicer enzyme responsible for miRNA formation. Among other functions, miRNA regulates gene expression post-transcriptionally. Previous work by Dr. Anslow in her animal models showed significantly higher rates of VUR in mice that lack the Dicer enzyme, implicating miRNAs for the first time in the development of VUR.

“We have good evidence for miRNAs role in VUR and the broader spectrum of kidney development. My continuing research is working to pinpoint which miRNAs are responsible for VUR development and the signaling pathways in which they work,” says Dr. Anslow.

New Research Summary

Dr. Anslow's new research examined what role miRNAs play during the development of ureteric bud induction and formation of the vesicoureteral junction (VUJ). Normal development of these structures is key to the prevention of VUR.

It is known that ureteric bud induction is regulated by signaling pathways from the peri-Wolffian duct stromal cells, but what has been unclear is if miRNAs expressed in the peri-Wolffian duct stroma have any influence or regulatory properties that, if disrupted or otherwise modulated, could negatively affect either or both ureteric bud induction or the VUJ.

To test this hypothesis, Dr. Anslow and colleagues created a knockout mouse model with no miRNA expression in the critical peri-Wolffian duct stroma. They then examined the ureteric bud induction for defects, and also the presence of VUR by way of cystogram, along with screening for any potential gene expression irregularities that may have arisen from the knockout of miRNAs.

"Our study found that while gene expression seemed to be unaffected in the knockout model, there were marked changes in the ureteric bud induction sites, and the knockout animals experienced high rates of VUR compared to our control groups. This tells us that, indeed, miRNAs play a critical role in the peri-Wolffian duct stroma to regulate normal development and prevent VUR. We will be further exploring aspects of miRNA regulation and pathways in our continuing VUR research," says Dr. Anslow.

Reference

Anslow MJ, Bodnar AJ, Cerqueira DM, Bushnell D, Shrom BE, Sims-Lucas S, Bates CM, Ho J. Increased Rates of Vesicoureteral Reflux in Mice From Deletion of Dicer in the Peri-Wolffian Duct Stroma. Pediatr Res. 2020; 88: 382–390.