The Enigmatic Role of Serum & Glucocorticoid Inducible Kinase 1 in the Endometrium.

The nutritional status of the mother is an important factor that affects fetal programming ( Langley-Evans et al., 1994 ; Vehaskari et al., 2001 ; Woods et al., 2001 ; Lamireau et al., 2002 ; Manning et al., 2002 ; McMullen and Langley-Evans, 2005 ; Welham et al., 2005 ; Maria Pereira Pires et al., 2006 ; Pladys et al., 2006 ; Zambrano et al., 2006 ; Hocher, 2007 ; Dörsam et al., 2019 ; Rughani et al., 2020 ; Zhou et al., 2020 ). To investigate the impact of SGK1 on fetal programming and hypertension (blood pressure), Rexhepaj et al., mated wild-type ( sgk1 +/+ ) male mice with sgk1 –/– female mice, and sgk1 –/– males with sgk1 +/+ females, resulting in heterozygotic (sgk1 –/+ ) offspring in both cases ( Rexhepaj et al., 2008 ). During mating and pregnancy, the animals were subjected to low protein diet (8%). As a result prenatal protein restriction of wild type ( sgk1 +/+ ) maternal mice led to offspring with a slower weight gain and significantly higher blood pressure after birth ( Rexhepaj et al., 2008 ). Thus, maternal signals mediated by SGK1 play a decisive role in fetal programming of hypertension induced by prenatal protein restriction ( Rexhepaj et al., 2008 ). In a rat model, the miR-200 family and their associated mRNAs from vascular specimens from the offspring of dams undernourished during gestation were dysregulated ( Khorram et al., 2010 ). Interestingly, these changes in miR-200 were still prominent 1 year after birth. Bioinformatics analyses obtained from the miRbase server showed that there is a paired seed region for miR-200 on the SGK1 3′UTR. It is therefore tempting to speculate that miR-200 could directly modulate SGK1 expression as an upstream regulator thus, modifying the function of endothelial cells or angiogenic signaling during pregnancy. SGK1 also participates in embryonic neoangiogenesis by phosphorylating its physiological substrate NDRG1 and modulating expression of angiogenic factor VEGFA via the NFκB signaling axis ( Zygmunt et al., 2003 ; Zarrinpashneh et al., 2013 ; Lou et al., 2016 ). Also, SGK1 plays a role in vascular remodeling in angiogenesis by regulating the expression of notch-signaling genes and arterial markers Efnb2 and Nrp1 ( Catela et al., 2010 ). Given this, loss of maternal SGK1 may contribute to a reduction in endometrial vessel development, thereby contributing to growth restriction (IGUR), thus a lower pup weight. However, to prove this conjecture more investigations are essential to better appreciate the function of endometrial SGK1 and angiogenesis. Thus, these studies propose that maternal signals facilitated by SGK1 have a substantial role to play in in-utero programming of fetal blood pressure induced by a restricted (maternal) protein diet during pregnancy.

All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.

Despite years of research, we still lack clarity about how the endometrium supports implantation and the maintenance of an ensuing pregnancy. Though, several potential biomarkers of endometrial receptivity have been proposed, we still lack the in-depth theoretical knowledge to design targeted therapies for infertility. The numbers of infertility patients are staggering, ∼15% of couples cannot conceive and ∼30% of established pregnancies are lost, and these numbers are rising ( Teklenburg et al., 2010 ). Thus, there is a crucial need for development in reproductive medicine both at the ‘bench and bedside’. Studies addressing human reproduction face many challenges, including the ethical unfeasibility of obtaining samples in normal gestation to study implantation and very early pregnancy in humans. Murine studies have been instrumental in shedding light into the intricacies of embryo implantation and pregnancy. However, the major hurdle is in translating the key molecules found from murine models to humans. In the endometrium of humans and mice, SGK1 influences reproductive success by fine balancing expression and activity at the preimplantation stage and in the decidualizing stroma. SGK1s’ clinical implication in fertility and pregnancy loss makes it a potential target for therapeutic intervention. In particular, as the transient decline of SGK1 is beneficial for successful implantation, commercial SGK1 inhibitors, such as EMD638683, GSK650394, or the new SGK1 inhibitor, named SI113, might also be considered for treatment of infertility to aid patients who undergo IVF at the mid-secretory phase of the cycle or as a non-hormonal contraceptive. Critically, most of the data presented are based on cell-lines and the fact that SGK1 deficiency (knock out), in vivo , has minimal consequences for normal homeostasis. These studies associate SGK1 activation to specific pathways are rather restricted and often susceptible to caveats, including the use of overexpression (e.g., plasmid DNA) systems and the obvious lack of a multi-cellular environment. Current and future efforts, notably utilizing genetically engineered or uterine specific mouse models, shRNA-based cell systems, organoids or organ-on-a-chip methodologies ( Politi et al., 2004 ; Gnecco et al., 2017 ; Hibaoui and Feki, 2020 ) will facilitate progress and delineate the signaling molecules and pathways that are directly and specifically controlled by SGK1 in the endometrium and eventually provide more insight into the intricate maternal-fetal labyrinthine.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Globally, 90,000,000 couples (one in seven) have difficulties conceiving, and in excess of 30,000 IVF treatment cycles fail annually in Germany alone, usually because of embryo implantation failure and a further 15% of clinically recognized pregnancies go on to miscarry ( European IVF-Monitoring Consortium (EIM) for the European Society of Human Reproduction and Embryology [ESHRE] et al., 2016 ). With delay in childbearing age and factors influencing fertility such as obesity, there will be a greater dependency on IVF. By 2027, the socio-economic impact for IVF (and its subsidiaries) is estimated to exceed $37.7 Billion USD ( Research, 2020 ). These statistics are startling, but these numbers are likely to increase. Therefore, efforts have been made in this direction in recent years to try to realize novel methods for detection of biomarkers and drug targets. This review has presented evidence regarding SGK1 as potential endometrial regulator. Dysregulated SGK1 is implicated in impaired endometrial receptivity, implantation failure, endometriosis and in fetal programming. In fact, there is currently great interest in identifying gene targets that can be used as markers for the early detection of endometrial disorders and fertility. However, the implications of the findings described throughout this review need to be confirmed in large clinical trials before they become a real approach in daily clinical practice for assessing embryonic and endometrial health, and thereby increasing pregnancy rates per transfer after IVF. In summary, maternal SGK1 plays a decisive role in mediating initial interaction of the implanting blastocyst with the endometrium, helps to maintain functional feto-maternal interface for pregnancy survival and contributes to fetal programming. It is hoped that future studies will lead to improved diagnostic and predictive tools that will assist in patient stratification and ultimately, improved pregnancy outcomes.

Serum and glucocorticoid-inducible kinase 1 (SGK1) was discovered as an immediate early gene, transcriptionally induced in rat mammary cancer cells by glucocorticoids and serum ( Webster et al., 1993 ). SGK1 is evolutionarily conserved and is found in almost all tissues ( Arencibia et al., 2013 ). However, it is strictly transcriptionally and post-transcriptionally regulated ( Waldegger et al., 1997 ; Brickley et al., 2002 ; Belova et al., 2006 ; Lang et al., 2006 ; Di Cristofano, 2017 ). Enhanced activity of SGK1 plays a decisive role in the pathophysiology of several clinical disorders, such as metabolic syndrome, fibrosis, vascular occlusion, tissue calcification, neurodegeneration, inflammation, autoimmune disease, malignancy and compromised female reproduction ( Salker et al., 2011 ; Harries et al., 2012 ; Kleinewietfeld et al., 2013 ; Lang and Voelkl, 2013 ; Pelzl et al., 2017 ). Twin studies have disclosed a gain-of-function SGK1 gene variant in intron 6 [I6CC] and in exon 8 [E8CC/CT] ( Busjahn et al., 2004 ). The prevalence of the I6C/E8CC/CT genotype was approximately 3–5% in Caucasians and 10% in African/Asian population ( Busjahn et al., 2004 ; Schwab et al., 2008 ). Individuals with the SGK1 polymorphism were associated with moderately enhanced occurrence of hypertension, shortened QT interval in electrocardiograms, stroke, obesity and diabetes ( Busjahn et al., 2004 ; Schwab et al., 2008 ). A recent paper also reported that SGK1 variants were associated with chronic heart disease and depression in the Chinese Han population ( Han et al., 2019 ). The present review provides a short synopsis of the mechanisms regulating SGK1 expression and activity, the molecular SGK1 targets as well as the SGK1-dependent cell functions and survival. We also highlight the role of SGK1 in obesity and diabetes, and in inflammatory diseases such as endometriosis. Most importantly, the review amplifies on the involvement of SGK1 in the regulation of embryo implantation, embryo survival and fetal programming.