title: Hyperoxia exposure impairs nephrogenesis in the neonatal rat: role of HIF-1α.
abstract: Preterm neonates are exposed at birth to high oxygen concentrations relative to the intrauterine environment. We have previously shown in a rat model that a hyperoxic insult results in a reduced nephron number in adulthood. Therefore, the aim of this study was to determine the effects of transient neonatal hyperoxia exposure on nephrogenesis. Sprague-Dawley rat pups were raised in 80% O2 or room air from P3 to P10. Pups (n = 12/group, 6 males and 6 females) were sacrificed at P5 (during active nephrogenesis) and at P10 (after the completion of nephrogenesis). Hyperoxia exposure resulted in a significant reduction in both nephrogenic zone width and glomerular diameter at P5, and a significantly increased apoptotic cell count; however, nephron number at P10 was not affected. HIF-1α expression in the developing kidney was significantly reduced following hyperoxia exposure. Systemic administration of the HIF-1α stabilizer dimethyloxalylglycine (DMOG) resulted in enhanced expression of HIF-1α and improved nephrogenesis: kidneys from hyperoxia-exposed pups treated with DMOG exhibited a nephrogenic zone width and glomerular diameter similar to room-air controls. These findings demonstrate that neonatal hyperoxia exposure results in impaired nephrogenesis, which may be at least in part HIF-1α-mediated. Although nephron number was not significantly reduced at the completion of nephrogenesis, early indicators of maldevelopment suggest the potential for accelerated nephron loss in adulthood. Overall, this study supports the premise that prematurely born neonates exposed to high oxygen levels after birth are vulnerable to impaired renal development.
authors.affiliation: Sainte-Justine University Hospital and Research Center, and the Department of Pediatrics, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Constantin R
authors.initials: CR
authors.lastname: Popescu
authors.affiliation: Sainte-Justine University Hospital and Research Center, and the Department of Pediatrics, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Megan R
authors.initials: MR
authors.lastname: Sutherland
authors.affiliation: Sainte-Justine University Hospital and Research Center, and the Department of Pediatrics, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Anik
authors.initials: A
authors.lastname: Cloutier
authors.affiliation: Sainte-Justine University Hospital and Research Center, and the Department of Pediatrics, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Benoît
authors.affiliation: Sainte-Justine University Hospital and Research Center, and the Department of Pediatrics, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Mariane
authors.initials: M
authors.lastname: Bertagnolli
authors.affiliation: Sainte-Justine University Hospital and Research Center, and the Department of Pediatrics, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Catherine
authors.initials: C
authors.lastname: Yzydorczyk
authors.affiliation: Sainte-Justine University Hospital and Research Center, and the Department of Pediatrics, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Germain
authors.affiliation: Sainte-Justine University Hospital and Research Center, and the Department of Pediatrics, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Véronique
authors.initials: V
authors.lastname: Phan
authors.affiliation: INSERM U872, Centre de Recherche des Cordeliers, Université Pierre et Marie Curie - Paris 6, and Université Paris Descartes UMR S 872, Paris, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Lelièvre-Pegorier
authors.affiliation: Sainte-Justine University Hospital and Research Center, and the Department of Pathology, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Hervé
authors.initials: H
authors.lastname: Sartelet
authors.affiliation: Sainte-Justine University Hospital and Research Center, and the Department of Pediatrics, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Anne Monique
authors.initials: AM
authors.lastname: Nuyt
mesh_terms: D000600:Amino Acids, Dicarboxylic / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D005260:Female; D018496:Hyperoxia / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007678:Kidney Glomerulus / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000600:Amino Acids, Dicarboxylic; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C040947:oxalylglycine