Increased rates of vesicoureteral reflux in mice from deletion of Dicer in the peri-Wolffian duct stroma.
Animals
Apoptosis
Crosses, Genetic
DEAD-box RNA Helicases
/ genetics
Female
Fluorescence
Gene Deletion
Gene Expression Regulation, Developmental
Image Processing, Computer-Assisted
Imaging, Three-Dimensional
Kidney
/ metabolism
Male
Mesoderm
/ pathology
Mice
Mice, Knockout
Mice, Transgenic
MicroRNAs
/ metabolism
Microscopy, Fluorescence
Mutation
Ribonuclease III
/ genetics
Ureter
/ metabolism
Urinary Bladder
/ metabolism
Vesico-Ureteral Reflux
/ genetics
Wolffian Ducts
/ metabolism
Journal
Pediatric research
ISSN: 1530-0447
Titre abrégé: Pediatr Res
Pays: United States
ID NLM: 0100714
Informations de publication
Date de publication:
09 2020
09 2020
Historique:
received:
28
10
2019
accepted:
16
01
2020
revised:
13
01
2020
pubmed:
6
2
2020
medline:
24
8
2021
entrez:
5
2
2020
Statut:
ppublish
Résumé
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.
Sections du résumé
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.
Identifiants
pubmed: 32015493
doi: 10.1038/s41390-020-0788-7
pii: 10.1038/s41390-020-0788-7
pmc: PMC7396288
mid: NIHMS1551694
doi:
Substances chimiques
MicroRNAs
0
Dicer1 protein, mouse
EC 3.1.26.3
Ribonuclease III
EC 3.1.26.3
DEAD-box RNA Helicases
EC 3.6.4.13
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
382-390Subventions
Organisme : NIDDK NIH HHS
ID : R56 DK121758
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK079307
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK121758
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK095748
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK104374
Pays : United States
Organisme : NIDDK NIH HHS
ID : K01 DK096996
Pays : United States
Organisme : NIDDK NIH HHS
ID : T32 DK091202
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK103776
Pays : United States
Organisme : NIDDK NIH HHS
ID : R03 DK110503
Pays : United States
Organisme : NICHD NIH HHS
ID : K12 HD052892
Pays : United States
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