Reduction in Maternal Circulating Ouabain Impairs Offspring Growth and Kidney Development
Reduction in Maternal Circulating Ouabain Impairs Offspring Growth and Kidney Development
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DOI：
10.1681/asn.2014020130
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发表时间：
2015-05-01
影响因子：
13.6
通讯作者：
Lichtstein, David
中科院分区：
文献类型：
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作者：
Dvela-Levitt, Moran;Cohen-Ben Ami, Hagit;Lichtstein, David
哇巴因是一种存在于循环和各种组织中的类固醇，显示出影响培养物中各种细胞的生长和活力。为了测试这种类固醇对体内生长和活力的可能影响，我们研究了母体循环哇巴因对胎儿生长和器官发育的调节。我们表明，腹腔注射抗哇巴因抗体的怀孕小鼠导致循环哇巴因水平下降>80%。这种减少导致后代体重显著下降，伴随着后代心脏增大以及肾脏和肝脏生长受到抑制。肾脏生长抑制表现为肾单位的大小和数量减少。母体循环哇巴因减少后，肾脏细胞周期蛋白D1的表达减少，Na+，K+-ATP酶α 1亚型的表达增加。此外，还检测到增殖信号包括ERK 1/2、p-90 RSK、Akt、PCNA和Ki-67的升高，以及凋亡因子如Bax、caspase-3和TUNEL的减少。在人类怀孕期间，母体循环中的哇巴因水平增加，并且在胎盘中发现类固醇的最高浓度。此外，小于胎龄儿的妇女的循环哇巴因水平显著低于正常胎龄儿的妇女。这些结果支持哇巴因是一种生长因子的观点，并表明在怀孕期间这种激素浓度的降低可能会增加生长和肾脏发育受损的风险。
Ouabain, a steroid present in the circulation and in various tissues, was shown to affect the growth and viability of various cells in culture. To test for the possible influence of this steroid on growth and viability in vivo, we investigated the involvement of maternal circulating ouabain in the regulation of fetal growth and organ development. We show that intraperitoneal administration of anti-ouabain antibodies to pregnant mice resulted in a >80% decline in the circulating ouabain level. This reduction caused a significant decrease in offspring body weight, accompanied by enlargement of the offspring heart and inhibition of kidney and liver growth. Kidney growth inhibition was manifested by a decrease in the size and number of nephrons. After the reduction in maternal circulating ouabain, kidney expression of cyclin D1 was reduced and the expression of the alpha 1 isoform of the Na+, K+-ATPase was increased. In addition, the elevation of proliferation signals including ERK1/2, p-90RSK, Akt, PCNA, and Ki-67, and a reduction in apoptotic factors such as Bax, caspase-3, and TUNEL were detected. During human pregnancy, the circulating maternal ouabain level increased and the highest concentration of the steroid was found in the placenta.. Furthermore, circulating ouabain levels in women with small-for-gestational age neonates were significantly lower than the levels in women with normal-for-gestational age newborns. These results support the notion that ouabain is a growth factor and suggest that a reduction in the concentration of this hormone during pregnancy may increase the risk of impaired growth and kidney development.