title: Neonatal vascularization and oxygen tension regulate appropriate perinatal renal medulla/papilla maturation.
abstract: Congenital medullary dysplasia with obstructive nephropathy is a common congenital disorder observed in paediatric patients and represents the foremost cause of renal failure. However, the molecular processes regulating normal papillary outgrowth during the postnatal period are unclear. In this study, transcriptional profiling of the renal medulla across postnatal development revealed enrichment of non-canonical Wnt signalling, vascular development, and planar cell polarity genes, all of which may contribute to perinatal medulla/papilla maturation. These pathways were investigated in a model of papillary hypoplasia with functional obstruction, the Crim1(KST264/KST264) transgenic mouse. Postnatal elongation of the renal papilla via convergent extension was unaffected in the Crim1(KST264/KST264) hypoplastic renal papilla. In contrast, these mice displayed a disorganized papillary vascular network, tissue hypoxia, and elevated Vegfa expression. In addition, we demonstrate the involvement of accompanying systemic hypoxia arising from placental insufficiency, in appropriate papillary maturation. In conclusion, this study highlights the requirement for normal vascular development in collecting duct patterning, development of appropriate nephron architecture, and perinatal papillary maturation, such that disturbances contribute to obstructive nephropathy.
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia.|Rangos Research Center, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA.|School of Medicine, Department of Pediatrics, Division of Nephrology, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Yu Leng
authors.identifier: http://orcid.org/0000-0002-3428-8669
authors.initials: YL
authors.lastname: Phua
authors.affiliation: Centre for Developmental Biology, University Paul Sabatier, Toulouse, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Gilbert
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia.|Department of Anatomy and Neuroscience, University of Melbourne, Melbourne, VIC, Australia.|Department of Pediatrics, University of Melbourne, Melbourne, VIC, Australia.
authors.forename: Alexander
authors.initials: A
authors.lastname: Combes
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia.
authors.forename: Lorine
authors.initials: L
authors.lastname: Wilkinson
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia.|Department of Pediatrics, University of Melbourne, Melbourne, VIC, Australia.|Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, VIC, Australia.
authors.forename: Melissa H
authors.initials: MH
authors.lastname: Little
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D052004:Bone Morphogenetic Protein Receptors / Q000235:genetics / Q000378:metabolism; D019295:Computational Biology; D004195:Disease Models, Animal; D005311:Fetal Hypoxia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D005865:Gestational Age; D007679:Kidney Medulla / Q000098:blood supply* / Q000378:metabolism* / Q000473:pathology; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000235:genetics; D010100:Oxygen / Q000378:metabolism*; D010641:Phenotype; D014564:Urogenital Abnormalities / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D014718:Vesico-Ureteral Reflux / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D060449:Wnt Signaling Pathway / Q000235:genetics
chemical_list: C518411:Crim1 protein, mouse; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D052004:Bone Morphogenetic Protein Receptors; D010100:Oxygen
keywords: Crim1; convergent extension; hypoxia; medullary vasculature; non-canonical Wnt signalling; renal papilla