title: Deletion of the miR-143/145 cluster leads to hydronephrosis in mice.
abstract: Obstructive nephropathy, the leading cause of kidney failure in children, can be anatomic or functional. The underlying causes of functional hydronephrosis are not well understood. miRNAs, which are small noncoding RNAs, regulate gene expression at the post-transcriptional level. We found that miR-145-5p, a member of the miR-143/145 cluster that is highly expressed in smooth muscle cells of the renal vasculature, was present in the pelvicalyceal system and the ureter. To evaluate whether the miR-143/145 cluster is involved in urinary tract function we performed morphologic, functional, and gene expression studies in mice carrying a whole-body deletion of miR-143/145. miR-143/145-deficient mice developed hydronephrosis, characterized by severe papillary atrophy and dilatation of the pelvicalyceal system without obvious physical obstruction. Moreover, mutant mice showed abnormal ureteral peristalsis. The number of ureter contractions was significantly higher in miR-143/145-deficient mice. Peristalsis was replaced by incomplete, short, and more frequent contractions that failed to completely propagate in a proximal-distal direction. Microarray analysis showed 108 differentially expressed genes in ureters of miR-143/145-deficient mice. Ninety genes were up-regulated and 18 genes were down-regulated, including genes with potential regulatory roles in smooth muscle contraction and extracellular matrix-receptor interaction. We show that miR-143/145 are important for the normal peristalsis of the ureter and report an association between the expression of these miRNAs and hydronephrosis.
authors.affiliation: Department of Pediatrics, School of Medicine, University of Virginia, Charlottesville, Virginia.
authors.forename: Silvia
authors.initials: S
authors.lastname: Medrano
authors.affiliation: Department of Pediatrics, School of Medicine, University of Virginia, Charlottesville, Virginia.
authors.forename: Maria Luisa S
authors.initials: ML
authors.lastname: Sequeira-Lopez
authors.affiliation: Department of Pediatrics, School of Medicine, University of Virginia, Charlottesville, Virginia. Electronic address: rg@virginia.edu.
authors.forename: R Ariel
authors.initials: RA
authors.lastname: Gomez
mesh_terms: D000818:Animals; D001806:Blood Urea Nitrogen; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D005260:Female; D017353:Gene Deletion; D006579:Heterozygote; D006869:Hydronephrosis / Q000235:genetics* / Q000378:metabolism; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics*; D009130:Muscle, Smooth / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010528:Peristalsis; D014513:Ureter / Q000378:metabolism
chemical_list: C543499:MIRN145a microRNA, mouse; D035683:MicroRNAs; C532884:MIRN143 microRNA, mouse; D003404:Creatinine