title: Prorenin receptor is critical for nephron progenitors.
abstract: Deficient nephrogenesis is the major factor contributing to renal hypoplasia defined as abnormally small kidneys. Nephron induction during kidney development is driven by reciprocal interactions between progenitor cells of the cap mesenchyme (CM) and the ureteric bud (UB). The prorenin receptor (PRR) is a receptor for renin and prorenin, and an accessory subunit of the vacuolar proton pump H(+)-ATPase. Global loss of PRR is lethal in mice and PRR mutations are associated with a high blood pressure, left ventricular hypertrophy and X-linked mental retardation in humans. To circumvent lethality of the ubiquitous PRR mutation in mice and to determine the potential role of the PRR in nephrogenesis, we generated a mouse model with a conditional deletion of the PRR in Six2(+) nephron progenitors and their epithelial derivatives (Six2(PRR-/-)). Targeted ablation of PRR in Six2(+) nephron progenitors caused a marked decrease in the number of developing nephrons, small cystic kidneys and podocyte foot process effacement at birth, and early postnatal death. Reduced congenital nephron endowment resulted from premature depletion of nephron progenitor cell population due to impaired progenitor cell proliferation and loss of normal molecular inductive response to canonical Wnt/β-catenin signaling within the metanephric mesenchyme. At 2 months of age, heterozygous Six2(PRR+/-) mice exhibited focal glomerulosclerosis, decreased kidney function and massive proteinuria. Collectively, these findings demonstrate a cell-autonomous requirement for the PRR within nephron progenitors for progenitor maintenance, progression of nephrogenesis, normal kidney development and function.
authors.affiliation: Department of Pediatrics, Department of Pathology, Tulane University School of Medicine, New Orleans, LA 70112, USA.
authors.forename: Renfang
authors.initials: R
authors.lastname: Song
authors.affiliation: Department of Pediatrics, Department of Pathology, Tulane University School of Medicine, New Orleans, LA 70112, USA.
authors.forename: Graeme
authors.initials: G
authors.lastname: Preston
authors.affiliation: Department of Pediatrics, Department of Pathology, Tulane University School of Medicine, New Orleans, LA 70112, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Kidd
authors.affiliation: Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15201, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Bushnell
authors.affiliation: Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15201, USA.
authors.forename: Sunder
authors.initials: S
authors.lastname: Sims-Lucas
authors.affiliation: Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15201, USA.
authors.forename: Carlton M
authors.initials: CM
authors.lastname: Bates
authors.affiliation: Department of Pediatrics, Department of Pathology, Tulane University School of Medicine, New Orleans, LA 70112, USA. Electronic address: iiosipi@tulane.edu.
authors.forename: Ihor V
authors.initials: IV
authors.lastname: Yosypiv
mesh_terms: D000818:Animals; D016923:Cell Death; D049109:Cell Proliferation; D004848:Epithelium / Q000196:embryology; D017353:Gene Deletion; D018628:Gene Dosage; D018390:Gene Targeting; D018398:Homeodomain Proteins / Q000378:metabolism; D007668:Kidney / Q000166:cytology / Q000196:embryology / Q000503:physiopathology; D052177:Kidney Diseases, Cystic / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D008648:Mesoderm / Q000166:cytology / Q000196:embryology; D051379:Mice; D009399:Nephrons / Q000166:cytology*; D038081:Organogenesis; D050199:Podocytes / Q000378:metabolism / Q000648:ultrastructure; D011507:Proteinuria / Q000150:complications / Q000503:physiopathology; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D000093342:Prorenin Receptor
chemical_list: D018398:Homeodomain Proteins; D011956:Receptors, Cell Surface; C497420:Six2 protein, mouse; D014157:Transcription Factors; D000093342:Prorenin Receptor
keywords: Kidney development; Nephrogenesis; Nephron progenitor cells; Prorenin receptor; Proteinuria; Renal hypodysplasia