Popescu Constantin R, Sutherland Megan R, Cloutier Anik, Benoît Geneviève, Bertagnolli Mariane, Yzydorczyk Catherine, Germain Nathalie, Phan Véronique, Lelièvre-Pegorier Martine, Sartelet Hervé, Nuyt Anne Monique
Sainte-Justine University Hospital and Research Center, and the Department of Pediatrics, Université de Montréal, Montreal, Quebec, Canada.
INSERM U872, Centre de Recherche des Cordeliers, Université Pierre et Marie Curie - Paris 6, and Université Paris Descartes UMR S 872, Paris, France.
PLoS One. 2013 Dec 17;8(12):e82421. doi: 10.1371/journal.pone.0082421. eCollection 2013.
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.
与子宫内环境相比，早产新生儿出生时暴露于高氧浓度环境中。我们之前在大鼠模型中表明，高氧损伤会导致成年后肾单位数量减少。因此，本研究的目的是确定短暂性新生儿高氧暴露对肾发生的影响。将Sprague-Dawley大鼠幼崽从出生后第3天（P3）至第10天（P10）饲养在80%氧气或室内空气中。在P5（肾发生活跃期）和P10（肾发生完成后）处死幼崽（每组n = 12只，6只雄性和6只雌性）。高氧暴露导致P5时肾发生区宽度和肾小球直径显著减小，凋亡细胞计数显著增加；然而，P10时的肾单位数量未受影响。高氧暴露后，发育中肾脏的HIF-1α表达显著降低。全身给予HIF-1α稳定剂二甲基草酰甘氨酸（DMOG）可导致HIF-1α表达增强和肾发生改善：用DMOG治疗的高氧暴露幼崽的肾脏，其肾发生区宽度和肾小球直径与室内空气对照组相似。这些发现表明，新生儿高氧暴露会导致肾发生受损，这可能至少部分是由HIF-1α介导的。尽管在肾发生完成时肾单位数量没有显著减少，但发育不良的早期指标表明成年后肾单位丢失加速的可能性。总体而言，本研究支持这样一个前提，即出生后暴露于高氧水平的早产新生儿易受肾脏发育受损的影响。
