title: Renal developmental defects resulting from in utero hypoxia are associated with suppression of ureteric β-catenin signaling.
abstract: Gestational stressors, including glucocorticoids and protein restriction, can affect kidney development and hence final nephron number. Since hypoxia is a common insult during pregnancy, we studied the influence of oxygen tension on kidney development in models designed to represent a pathological hypoxic insult. In vivo mouse models of moderate, transient, midgestational (12% O₂, 48 h, 12.5 dpc) or severe, acute, early-gestational (5.5-7.5% O₂, 8 h, 9.5-10.5 dpc) hypoxia were developed. The embryo itself is known to mature under hypoxic conditions with embryonic tissue levels of oxygen estimated to be 5%-8% (physiological hypoxia) when the mother is exposed to ambient normoxia. Both in vivo models generated phenotypes seen in patients with congenital anomalies of the kidney and urinary tract (CAKUT). Severe, acute, early hypoxia resulted in duplex kidney, while moderate, transient, midgestational hypoxia permanently reduced ureteric branching and nephron formation. Both models displayed hypoxia-induced reductions in β-catenin signaling within the ureteric tree and suppression of the downstream target gene, Ccnd1. Thus, we show a link between gestational hypoxia and CAKUT, the phenotype of which varies with timing, duration, and severity of the hypoxic insult.
authors.affiliation: Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia.
authors.forename: Lorine J
authors.initials: LJ
authors.lastname: Wilkinson
authors.affiliation: Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia.
authors.forename: Cailda S
authors.initials: CS
authors.lastname: Neal
authors.affiliation: School of Biomedical Sciences, University of Queensland, Brisbane, QLD, Australia.
authors.forename: Reetu R
authors.initials: RR
authors.lastname: Singh
authors.affiliation: 1] Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, Sydney, NSW, Australia [2] Faculty of Medicine, St Vincent's Clinical School, University of New South Wales, Sydney, NSW, Australia.
authors.forename: Duncan B
authors.initials: DB
authors.lastname: Sparrow
authors.affiliation: Centre for Advanced Imaging, University of Queensland, Brisbane, QLD, Australia.
authors.forename: Nyoman D
authors.initials: ND
authors.lastname: Kurniawan
authors.affiliation: Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia.
authors.forename: Adler
authors.initials: A
authors.lastname: Ju
authors.affiliation: 1] Sydney Translational Imaging Laboratory, Sydney Medical School, University of Sydney, Sydney, NSW, Australia [2] Department of Radiology, Royal Prince Alfred Hospital, Sydney, NSW, Australia.
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Grieve
authors.affiliation: 1] Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, Sydney, NSW, Australia [2] Faculty of Medicine, St Vincent's Clinical School, University of New South Wales, Sydney, NSW, Australia [3] Faculty of Science, School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia.
authors.forename: Sally L
authors.initials: SL
authors.lastname: Dunwoodie
authors.affiliation: School of Biomedical Sciences, University of Queensland, Brisbane, QLD, Australia.
authors.forename: Karen M
authors.initials: KM
authors.lastname: Moritz
authors.affiliation: Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia.
authors.forename: Melissa H
authors.initials: MH
authors.lastname: Little
mesh_terms: D000818:Animals; D005260:Female; D005311:Fetal Hypoxia / Q000150:complications* / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007668:Kidney / Q000002:abnormalities*; D008822:Mice, Transgenic; D011247:Pregnancy; D014513:Ureter / Q000378:metabolism*; D014564:Urogenital Abnormalities / Q000209:etiology* / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051176:beta Catenin