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

• Published in: Nature medicine Vol. 17; no. 11; pp. 1509 - 1513
• Main Authors: Salker, Madhuri S, Christian, Mark, Steel, Jennifer H, Nautiyal, Jaya, Lavery, Stuart, Trew, Geoffrey, Webster, Zoe, Al-Sabbagh, Marwa, Puchchakayala, Goverdhan, Föller, Michael, Landles, Christian, Sharkey, Andrew M, Quenby, Siobhan, Aplin, John D, Regan, Lesley, Lang, Florian, Brosens, Jan J
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.11.2011; Nature Publishing Group
• Subjects: 631/208/199; 631/443/494; 692/699/2732; Animals; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cell Death; Cells, Cultured; Cellular biology; Deregulation; Embryo Implantation - physiology; Embryos; Endometrium; Endometrium - cytology; Endometrium - enzymology; Female; Gene expression; Genetic aspects; Humans; Immediate-Early Proteins - genetics; Immediate-Early Proteins - metabolism; Infectious Diseases; Infertility; Infertility, Female; Ion transport; Kinases; letter; Male; Metabolic Diseases; Mice; Mice, Inbred C57BL; Mice, Knockout; Miscarriage; Molecular Medicine; Neurosciences; Obstetrics; Oxidative Stress; Physiological aspects; Placenta - cytology; Placenta - physiology; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Protein kinases; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Risk factors; Stromal Cells - cytology; Stromal Cells - metabolism; United Kingdom
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/nm.2498

Jan Brosens and his colleagues have found that deregulation of a single kinase—SGK1, a kinase involved in fluid balance—in two distinct cellular compartments of the endometrium is linked to two different forms of reproductive failure in humans. Using gain- and loss-of-function approaches in mice, the group confirmed the importance of these expression changes in such pathologies. 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 , 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.