Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia.
School of Biomedical Sciences, University of Queensland, Brisbane, QLD, Australia.
Kidney Int. 2015 May;87(5):975-83. doi: 10.1038/ki.2014.394. Epub 2015 Jan 14.
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.
妊娠应激，包括糖皮质激素和蛋白质限制，可影响肾脏发育，从而影响终末肾单位数量。由于缺氧是妊娠期间常见的损伤因素，我们研究了氧张力对模拟病理性缺氧损伤模型中肾脏发育的影响。建立了中等程度、短暂、妊娠中期（12% O₂，48 h，12.5 dpc）或严重、急性、妊娠早期（5.5-7.5% O₂，8 h，9.5-10.5 dpc）缺氧的体内小鼠模型。众所周知，胚胎在缺氧条件下成熟，当母亲暴露于环境常氧中时，胚胎组织中的氧气水平估计为 5%-8%（生理性缺氧）。这两种体内模型都产生了先天性肾和泌尿道异常（CAKUT）患者的表型。严重、急性、早期缺氧导致双肾盂，而中等程度、短暂、妊娠中期缺氧则永久性地减少输尿管分支和肾单位形成。两种模型均显示输尿管树内β-连环蛋白信号的缺氧诱导减少，以及下游靶基因 Ccnd1 的抑制。因此，我们证明了妊娠缺氧与 CAKUT 之间存在联系，其表型随缺氧损伤的时间、持续时间和严重程度而变化。
