title: Prorenin receptor controls renal branching morphogenesis via Wnt/β-catenin signaling.
abstract: The prorenin receptor (PRR) is a receptor for renin and prorenin, and an accessory subunit of the vacuolar proton pump H+-ATPase. Renal branching morphogenesis, defined as growth and branching of the ureteric bud (UB), is essential for mammalian kidney development. Previously, we demonstrated that conditional ablation of thePRRin the UB inPRRUB-/-mice causes severe defects in UB branching, resulting in marked kidney hypoplasia at birth. Here, we investigated the UB transcriptome using whole genome-based analysis of gene expression in UB cells, FACS-isolated fromPRRUB-/-, and control kidneys at birth (P0) to determine the primary role of the PRR in terminal differentiation and growth of UB-derived collecting ducts. Three genes with expression in UB cells that previously shown to regulate UB branching morphogenesis, includingWnt9b, β-catenin, andFgfr2, were upregulated, whereas the expression ofWnt11,Bmp7,Etv4, andGfrα1was downregulated. We next demonstrated that infection of immortalized UB cells with shPRR in vitro or deletion of the UBPRRin double-transgenicPRRUB-/-/BatGal+mice, a reporter strain for β-catenin transcriptional activity, in vivo increases β-catenin activity in the UB epithelia. In addition to UB morphogenetic genes, the functional groups of differentially expressed genes within the downregulated gene set included genes involved in molecular transport, metabolic disease, amino acid metabolism, and energy production. Together, these data demonstrate that UB PRR performs essential functions during UB branching and collecting duct morphogenesis via control of a hierarchy of genes that control UB branching and terminal differentiation of the collecting duct cells.
authors.affiliation: Division of Pediatric Nephrology, Department of Pediatrics, Hypertension and Renal Center of Excellence, Tulane University School of Medicine, New Orleans, Lousiana.
authors.forename: Renfang
authors.initials: R
authors.lastname: Song
authors.affiliation: Division of Pediatric Nephrology, Department of Pediatrics, Hypertension and Renal Center of Excellence, Tulane University School of Medicine, New Orleans, Lousiana.
authors.forename: Adam
authors.initials: A
authors.lastname: Janssen
authors.affiliation: Division of Pediatric Nephrology, Department of Pediatrics, Hypertension and Renal Center of Excellence, Tulane University School of Medicine, New Orleans, Lousiana.
authors.forename: Yuwen
authors.initials: Y
authors.lastname: Li
authors.affiliation: Division of Pediatric Nephrology, Department of Pediatrics, Hypertension and Renal Center of Excellence, Tulane University School of Medicine, New Orleans, Lousiana.
authors.forename: Samir
authors.initials: S
authors.lastname: El-Dahr
authors.affiliation: Division of Pediatric Nephrology, Department of Pediatrics, Hypertension and Renal Center of Excellence, Tulane University School of Medicine, New Orleans, Lousiana iiosipi@tulane.edu.
authors.forename: Ihor V
authors.initials: IV
authors.lastname: Yosypiv
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D055419:Bone Morphogenetic Protein 7 / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage; D002469:Cell Separation / Q000379:methods; D019295:Computational Biology; D005434:Flow Cytometry; D020869:Gene Expression Profiling / Q000379:methods; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D005838:Genotype; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors / Q000235:genetics / Q000378:metabolism; D007685:Kidney Tubules, Collecting / Q000196:embryology / Q000378:metabolism*; D018345:Mice, Knockout; D009024:Morphogenesis; D010641:Phenotype; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics / Q000378:metabolism; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D059467:Transcriptome; D014513:Ureter / Q000196:embryology / Q000378:metabolism*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*; D000093342:Prorenin Receptor
chemical_list: D055419:Bone Morphogenetic Protein 7; C495267:CTNNB1 protein, mouse; C540571:Etv4 protein, mouse; C494988:Gfra1 protein, mouse; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D050783:Proto-Oncogene Proteins c-ets; D011956:Receptors, Cell Surface; D051153:Wnt Proteins; C508957:Wnt11 protein, mouse; C515303:Wnt9b protein, mouse; D051176:beta Catenin; C525820:bmp7 protein, mouse; C496354:Fgfr2 protein, mouse; D051497:Receptor, Fibroblast Growth Factor, Type 2; D000093342:Prorenin Receptor
keywords: kidney development; mice; prorenin receptor; renal hypodysplasia; ureteric bud; β-catenin