Rangos Research Center, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA.
Division of Nephrology, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Pediatr Res. 2020 Sep;88(3):382-390. doi: 10.1038/s41390-020-0788-7. Epub 2020 Feb 3.
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.
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.
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.
We found that miRNAs in the peri-Wolffian duct stroma are required for normal ureteric bud induction, VUJ formation, and prevention of VUR.
膀胱输尿管反流（VUR）是尿液反流进入肾脏的一种病症，与尿路感染和慢性肾病有关。膀胱输尿管连接处（VUJ）的完整性在很大程度上取决于输尿管芽从沃夫管的适当诱导。诱导受来自周围沃夫氏管基质的信号调节。我们评估了沃夫氏管周围基质中的 miRNAs 是否对输尿管的适当诱导、VUJ 的形成以及 VUR 的抑制是必要的。
我们生成了一种沃夫氏管周围基质中 miRNAs 缺失的小鼠。我们评估了胚胎的输尿管芽诱导缺陷和调节诱导的基因的表达。我们进行了膀胱造影以评估反流，并评估了产后小鼠的 VUJ。
突变胚胎的输尿管芽诱导部位相对于对照颅向移位。我们观察到调节诱导的已知基因的表达没有变化。虽然突变体在出生后早期是致死的，但它们的 VUR 发生率高于对照。反流的突变 VUJ 具有低插入输尿管和缩短的膀胱内隧道，与非反流小鼠相比。
我们发现沃夫氏管周围基质中的 miRNAs 对于正常的输尿管芽诱导、VUJ 的形成和 VUR 的预防是必需的。
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