Deletion of hypoxia-responsive microRNA-210 results in a sex-specific decrease in nephron number.

Low nephron number results in an increased risk of developing hypertension and chronic kidney disease. Intrauterine growth restriction is associated with a nephron deficit in humans, and is commonly caused by placental insufficiency, which results in fetal hypoxia. The underlying mechanisms by which hypoxia impacts kidney development are poorly understood. microRNA-210 is the most consistently induced microRNA in hypoxia and is known to promote cell survival in a hypoxic environment. In this study, the role of microRNA-210 in kidney development was evaluated using a global microRNA-210 knockout mouse. A male-specific 35% nephron deficit in microRNA-210 knockout mice was observed. Wnt/ß-catenin signaling, a pathway crucial for nephron differentiation, was misregulated in male kidneys with increased expression of the canonical Wnt target lymphoid enhancer binding factor 1. This coincided with increased expression of caspase-8-associated protein 2, a known microRNA-210 target and apoptosis signal transducer. Together, these data are consistent with a sex-specific requirement for microRNA-210 in kidney development.

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

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 vs. 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 vs. controls. Mutant VUJs that refluxed had low inserting ureters and shortened intravesicular tunnels vs. 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.