להלן מאמר המסביר את המנגנונים של הפעולה של אינזים זה ובין היתר מציין שהעבודה הקודמת שהוצגה נעשתה בעכברים ובבני אדם: Susan J Fisher & Linda C Giudice Affiliations Corresponding authors Nature Medicine 17,1348–1349(2011)doi:10.1038/nm.2549Published online 07 November 2011 Article tools PDF Citation Reprints Rights & permissions Article metrics A new study suggests that regulation of the serum- and glucocorticoid-regulated kinase (SGK1) is important for ensuring uterine receptivity and maintenance of pregnancy (pages 1509–1513). Additional work will be required to determine whether SGK1 could be potentially targeted to treat infertility and prevent miscarriage and whether it can be used as a biomarker. Despite decades of investigation, we still lack a clear mechanistic understanding of how the uterus supports implantation and maintains pregnancy, although numerous putative markers of receptivity to embryo implantation have been proposed1, 2, 3. It is clear that the hormones estradiol and progesterone have overarching roles in regulating uterine receptivity and differentiation (decidualization) of the stromal fibroblasts, a prerequisite for implantation1, 2, 3. Progesterone supplementation is prescribed widely to enhance implantation rates in infertility therapies using in vitro fertilization and embryo transfer and for sustaining pregnancy in cases of recurrent loss4. These empiric approaches prevail because we lack the theoretical underpinning to design more targeted therapies for infertility. Since ~15% of couples cannot conceive and ~30% of established pregnancies are lost5, there is a large clinical need for improvements in reproductive care. The powerful approach of mouse genetics has revealed many clues into the process of pregnancy, such as a requirement for maternal leukemia inhibitory factor (LIF) expression for implantation6. However, relatively little is known about whether mechanisms identified in mouse models are relevant to human pregnancy establishment and loss. In this issue of Nature Medicine, Salker et al.7 present data from humans and mouse models to support the theory that deregulated expression of SGK1 causes reproductive failure. SGK1, which is ubiquitously expressed, regulates transport, hormone release, cell proliferation and apoptosis8. Previously, the authors found deregulated endometrial expression of SGK1 in infertile women9. Their current work highlights a dual role for SGK1 in preventing implantation failure and miscarriage and suggests that aberrant regulation of SGK1 may have different mechanistic consequences in these two distinct reproductive conditions (Fig. 1)7. Figure 1: Balancing SGK1 expression to regulate pregnancy. Using mouse models, Salker et al.7 show that the expression of SGK1 needs to be tightly regulated in the appropriate uterine compartment for a positive outcome in pregnancy. Decreased SGK1 expression in the decidua led to miscarriage, as normally this kinase protects against oxidative cell death of endometrial stromal fibroblasts. Increased SGK1 expression in the uterine luminal epithelium led to a failure of embryo implantation, possibly through defects in osmoregulation, a normal function of SGK1. However, the mechanistic underpinnings of these phenotypes associated with deregulation of SGK1 expression remain unknown and should be addressed in future studies. Full size image (112 KB) The authors found that SGK1 mRNA levels were higher in the uterine luminal epithelia of infertile women compared to fertile controls7. In contrast, endometrial SGK1 expression was lower in women who experienced recurrent pregnancy loss. Salker et al.7 then used a vector expressing a constitutively active SGK1 mutant or a control plasmid (injected 1.5 days post coitus) to investigate whether forcing SGK1 activity in the luminal epithelium of the mouse uterus interferes with embryo implantation. No implantation sites were detected in the experimental group. Consistent with the kinase's known role in osmoregulation, the authors found that expression of the epithelial sodium channel (ENaC) was upregulated in the SGK1-mutant mice7. They also observed downregulation of Nedd4-2, another SGK1 target, and a ubiquitin ligase that modulates transforming growth factor-β activity. The authors then studied the effects of loss of SGK1 on pregnancy and found that SGK1-null mice had the same number of implantation sites as wild-type mice but an approximate 30% incidence of spontaneous fetal loss7. In the SGK1-null mice, the implantation sites were smaller, and there was histological evidence of bleeding and immune cell infiltration associated with approximately half the embryos. Finally, Salker et al.7 investigated the effects of reduced SGK1 activity during decidualization of human endometrial stromal fibroblasts in vitro and showed that this kinase protects against oxidative cell death by inducing various scavengers of reactive oxygen species. If SGK1 has similar roles in mice and humans, it will be interesting to understand how this molecule functions in the larger context of other factors that regulate implantation and decidualization in mice (reviewed in ref. 10). In an initial effort to answer this question, the authors found that driving SGK1 activity in the luminal epithelium abolished or attenuated expression of a subset of genes that are involved in uterine receptivity, decidualization or both (for example, LIF, heparin-binding epidermal growth factor, Hoxa10), but not others (Indian hedgehog, Wnt4 and Bmp2)7. The role of SGK1 in decidualization has yet to be investigated in this mouse model. Therefore, numerous questions are left unanswered regarding how this molecule functions in promoting endometrial receptivity to implantation and in supporting pregnancy maintenance. Given that SGK1 lies downstream of phosphatidylinositide-3-kinase and the 3-phosphoinositide–dependent kinase and upstream of glycogen-synthase-kinase-3 (ref. 11), does it primarily function in the context of this pathway? As preparation of the uterus for pregnancy is orchestrated by a myriad of transcription factors (for example, Hmx3, Hoxa11, KLF9 and CoupTFII), can a physiological regulator work at this level? Does SGK1 influence growth by controlling any or all of the cell cycle genes that are required, in mice, for fertility, decidualization or both (for example, cyclin D3, p21 and hepatoma upregulated protein)? Other processes important in implantation and pregnancy maintenance include angiogenesis and protection of the decidua (and perhaps of the conceptus) from oxidative stress. The question arises whether there is a functional link between SGK1 and the cyclooxygenase 2–mediated prostaglandin circuitry that influences vascular endothelial growth factor and angiopoietin signals during decidual angiogenesis. Given that Salker et al.7 demonstrated that SGK1 prevents oxidative damage, it will be interesting to investigate whether its expression is modulated in response to oxygen tension. These types of studies will give important insights into whether SGK1 is a major driver of the molecular mechanisms that prepare the uterus for pregnancy or simply a passenger that, when deregulated, is associated with generalized failures in this process. Overall, the connection between deregulation of a sodium channel and infertility together with pregnancy loss is new. In this regard, microarray analyses have demonstrated that numerous solute and ion channels are regulated in the human endometrium across the menstrual cycle. These include transporters for amino acids, sulfate, electron transport, divalent and trivalent cations, metals, carboxylic acids, peptides10 and solute carrier proteins during decidualization of fibroblasts in the endometrial stroma11. However there is little information about their potential functions in uterine-specific pathways, which this study suggests is an important area of future investigation. Understanding the significance of the work of Salker et al.7 awaits the outcome of future translational studies. If SGK1 is a driver of implantation and decidualization, then it could become an important therapeutic target for the potential treatment of infertility. This molecule could also be a biomarker of uterine receptivity, and, if so, would be an important addition to the morphological criteria and small number of molecules such as LIF, αVβ3 integrin and glycodelin that are currently used for this purpose (reviewed in ref. 3). And because infertility therapies affect endometrial gene expression and synchronization of cellular differentiation, it will be important to assess how they affect SGK1 expression. These types of studies face many challenges, including the ethical impossibility of directly studying human implantation and very early pregnancy and the difficulty of obtaining the relevant samples throughout normal gestation. Therefore, this study also highlights the importance of establishing high-quality sample banks of uterine tissues for rapidly evaluating candidate biomarkers that could be used to predict pregnancy success.
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