Deregulation of the serum- and glucocorticoid-inducible kinase SGK1 in the endometrium causes reproductive failure
Deregulation of the serum- and glucocorticoid-inducible kinase SGK1 in the endometrium causes reproductive failure
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DOI：
10.1038/nm.2498
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发表时间：
2011-11-01
期刊：
影响因子：
82.9
通讯作者：
Brosens, Jan J.
中科院分区：
文献类型：
--
作者：
Salker, Madhuri S.;Christian, Mark;Brosens, Jan J.
不孕不育和反复妊娠丢失(RPL)是生殖失败的普遍但不同的原因，尽管进行了广泛的调查，但往往仍然无法解释(1，2)。对分泌中期子宫内膜样本的分析表明，SGK1是一种参与上皮离子转运和细胞存活的激酶(3-6)，在原因不明的不孕症中上调，最显著的是在子宫腔上皮中，但在患有RPL的妇女的子宫内膜中表达下调。为了确定这些观察的功能重要性，我们首先在小鼠子宫腔上皮中表达了一个结构性活性的SGK1突变体。这阻止了某些子宫内膜容受性基因的表达，扰乱了子宫积液的处理，并取消了胚胎植入。相比之下，SGK1(-/-)小鼠的着床没有受到阻碍，但怀孕通常会并发蜕膜-胎盘交界处出血，以及胎儿生长迟缓和随后死亡。与野生型小鼠相比，SGK1(-/-)小鼠对氧化应激防御相关基因的诱导存在严重的妊娠依赖性损伤。相对的SGK1缺乏也是RPL受试者的基质细胞去分化的一个标志，并使这些细胞对氧化细胞死亡敏感。因此，根据细胞隔间的不同，周期子宫内膜中SGK1活性的失控会干扰胚胎着床，导致不孕，或通过使母胎界面容易受到氧化损伤而导致妊娠并发症。
Infertility and recurrent pregnancy loss (RPL) are prevalent but distinct causes of reproductive failure that often remain unexplained despite extensive investigations(1,2). Analysis of midsecretory endometrial samples revealed that SGK1, a kinase involved in epithelial ion transport and cell survival(3-6), is upregulated in unexplained infertility, most prominently in the luminal epithelium, but downregulated in the endometrium of women suffering from RPL. To determine the functional importance of these observations, we first expressed a constitutively active SGK1 mutant in the luminal epithelium of the mouse uterus. This prevented expression of certain endometrial receptivity genes, perturbed uterine fluid handling and abolished embryo implantation. By contrast, implantation was unhindered in Sgk1(-/-) mice, but pregnancy was often complicated by bleeding at the decidual-placental interface and fetal growth retardation and subsequent demise. Compared to wild-type mice, Sgk1(-/-) mice had gross impairment of pregnancy-dependent induction of genes involved in oxidative stress defenses. Relative SGK1 deficiency was also a hallmark of decidualizing stromal cells from human subjects with RPL and sensitized these cells to oxidative cell death. Thus, depending on the cellular compartment, deregulated SGK1 activity in cycling endometrium interferes with embryo implantation, leading to infertility, or predisposes to pregnancy complications by rendering the feto-maternal interface vulnerable to oxidative damage.