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

Abstract

The serum-and glucocorticoid-inducible kinase 1 (SGK1) is subject to genetic up-regulation by diverse stimulators including glucocorticoids, mineralocorticoids, dehydration, ischemia, radiation and hyperosmotic shock. To become active, the expressed kinase requires phosphorylation, which is accomplished by PI3K/PDK1 and mTOR dependent signaling. SGK1 enhances the expression/activity of various transport proteins including Na + /K +-ATPase as well as ion-, glucose-, and amino acid-carriers in the plasma membrane. SGK1 can further up-regulate diverse ion channels, such as Na +-, Ca 2+-, K +-and Cl − channels. SGK1 regulates expression/activity of a wide variety of transcription factors (such as FKHRL1/Foxo3a, β-catenin, NFκB and p53). SGK1 thus contributes to the regulation of transport, glycolysis, angiogenesis, cell survival, immune regulation, cell migration, tissue fibrosis and tissue calcification. In this review we summarized the current findings that SGK1 plays a crucial function in the regulation of endometrial function. Specifically, it plays a dual role in the regulation of endometrial receptivity necessary for implantation and, subsequently in pregnancy maintenance. Furthermore, fetal programming of blood pressure regulation requires maternal SGK1. Underlying mechanisms are, however, still ill-defined and there is a substantial need for additional information to fully understand the role of SGK1 in the orchestration of embryo implantation, embryo survival and fetal programming.

Endogenous progesterone in unexplained infertility: a systematic review and meta-analysis

“…Serum and glucocorticoid-regulated kinase 1 (SGK1) is an enzyme in the serine/ threonine kinase family which plays a role in endometrial regulation for implantation and pregnancy maintenance [40]; although the exact mechanisms are unclear SGK1 gene expression rises through the secretory phase, correlating with rising serum progesterone levels. When samples of endometrium were incubated with progesterone and oestrogen, the exposure to progesterone doubled SGK1 mRNA compared to samples incubated in oestrogen which showed no increase [41] Progesterone-induced blocking factor (PIBF) PIBF is a progesterone-induced protein that reduces maternal immunological response to trophoblastic invasion.…”

Identification of differently expressed mRNAs by peripheral blood mononuclear cells in Vogt-Koyanagi-Harada disease

“…Glucocorticoid receptor, nuclear factor kappa-B, reticuloendotheliosis viral oncogene homolog, activating transcription factor 6 have been shown to bind the promotor of SGK1 . 39 It is evident that the regulation of SGK1 is quite complex and which mechanisms are exactly operational in VKH is unclear and deserves further study.…”

The role of serum-glucocorticoid regulated kinase 1 in reproductive viability: implications from prenatal programming and senescence

“…Moreover, a considerable number of reports have described the SGK1-activated channels and carriers in Xenopus laevis oocytes, including ENaC, voltage-gated Na + channel Nav1.5 (encoded by the SCN5A gene), voltage-gated potassium channels KCNQ1/KCNE1, Kv 4.3 and Kv1.5, epithelial Ca 2+ channel TRPV5 and TRPV6, Cl − channel ClC-Ka and ClC-2, cystic fibrosis transmembrane conductance regulator Cl − channel CFTR, amino acid transporter SN1, excitatory amino acid transporter (EAAT)1 and EAAT5, electrogenic Na + coupled dicarboxylate transporter NaDC-1, posttranslational modulators PEPT2, Na + -phosphate cotransporter NaPiIIb, and sodium-potassium adenosine triphosphatase (Na + /K + -ATPase) [ 4 , 31 , 50 – 52 ]. All of these ion transporters regulated by SGK1 have been involved in the membrane potential nutrient, transportation and ion homeostasis of oocytes, contributing to normal oogenesis.…”

“…In the placenta of intrauterine programmed gestational diabetes mellitus (GDM) rats, increased phosphorylation of SGK1 combined with other alterations in mTOR signaling apparently lead to fetal overgrowth in female offspring by inducing a pro-oxidant and pro-inflammatory intrauterine environment [ 87 , 88 ]. Concordantly, the offspring of wild type (SGK1 + / + ) female mice mated with SGK1 knockout (SGK1 − / − ) male mice had significantly higher blood pressure and slower weight gain postnatally following prenatal fasting, whereas the offspring of SGK1 − / − mothers had no such phenotypes [ 31 ]. Therefore, maternal signals mediated by SGK1 participate in the fetal programming of diabetes and hypertension, shedding light on the decisive role of SGK1 in the maternal side of fetal programming.…”

“…According to reports, excessive SGK1 in the luminal epithelium of the endometrium may disturb the delicate uterine luminal fluid (ULF) balance, leading to a hostile environment that prevents embryo implantation. Additionally, it may dysregulate endometrial receptivity genes, contributing to unexplained implantation failure in humans [ 31 ]. Since the risk of infertility, abortion and birth defects increased along with germline ages, the somatic health should be well sustained to support reproductive activities [ 89 ].…”