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Deregulation of the serum- and glucocorticoid-inducible kinase SGK1 in the endometrium causes reproductive failure

Abstract

Infertility and recurrent pregnancy loss (RPL) are prevalent but distinct causes of reproductive failure that often remain unexplained despite extensive investigations1,2. Analysis of midsecretory endometrial samples revealed that SGK1, a kinase involved in epithelial ion transport and cell survival3,4,5,6, 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.

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Figure 1: Deregulated SGK1 expression and activity is associated with infertility and RPL.
Figure 2: Increased SGK1 activity in the luminal epithelium blocks embryo implantation.
Figure 3: Spontaneous pregnancy loss in Sgk1−/− pregnant mice.
Figure 4: Lack of SGK1 activity in decidualizing cells enhances susceptibility to oxidative cell death.

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Acknowledgements

We are grateful to all the women who participated in this study. This work was further supported by funds to J.J.B. and M.C. from the Contraceptive Research and Development Program Consortium for Industrial Collaboration in Contraceptive Research (CIG-08-122), the UK National Institute for Health Research Biomedical Research Centre funding scheme and from the Genesis Research Trust (M.S.S.) We are grateful to M. Parker for his insightful suggestions.

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Contributions

M.C., F.L. and J.J.B. designed the research; M.S.S., J.H.S., J.N., Z.W., M.A.-S., G.P., M.F. and C.L. carried out the research; S.L., G.T., S.Q., L.R. and J.J.B. phenotyped the subjects and provided samples; M.S.S., A.M.S., J.D.A., M.C., F.L. and J.J.B. analyzed the data; and J.J.B. wrote the paper.

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Correspondence to Jan J Brosens.

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Supplementary Figures 1–14, Supplementary Table 1 and Supplementary Methods (PDF 963 kb)

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Salker, M., Christian, M., Steel, J. et al. Deregulation of the serum- and glucocorticoid-inducible kinase SGK1 in the endometrium causes reproductive failure. Nat Med 17, 1509–1513 (2011). https://doi.org/10.1038/nm.2498

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