The roles and regulatory mechanisms of serum and glucocorticoid-regulated kinase 1 in miscarriage and preeclampsia

Serum and glucocorticoid-regulated kinase 1 (SGK1) is a serine/threonine kinase belonging to the AGC kinase family. SGK1 is widely expressed in diverse tissues, whose expression and activity are regulated by numerous physiological and pathophysiological factors, including glucocorticoids, mineralocorticoids, dehydration, ischemia, hyperosmotic stress, and radiation therapy. Following activation of the phosphatidylinositide 3-kinase (PI3K) signaling pathway, SGK1 is phosphorylated at its hydrophobic motif by the mechanistic target of rapamycin complex 2 (mTORC2) and at its kinase domain by 3-phosphoinositide-dependent protein kinase-1 (PDK1), thereby inducing its activation. Activated SGK1 subsequently upregulates the expression of various ion channels, such as Na+, Ca2+, K+, and Cl- channels. Furthermore, SGK1 participates in regulating the expression and activity of multiple transcription factors (e.g., FKHRL1/FOXO3a, β-catenin, NF-κB, and p53), thereby influencing fundamental cellular processes including proliferation, survival, apoptosis, substance transport, glycolysis, and angiogenesis. Consequently, dysregulation of SGK1 expression or activity is implicated in the pathogenesis of various diseases, including hypertension, cancer, autoimmune disorders, and neurodegenerative diseases. Of particular note, SGK1 exhibits high expression in the human endometrial epithelium and is involved in the regulation of multiple aspects of pregnancy. This review summarizes the role of SGK1 in the pathogenesis of spontaneous abortion and preeclampsia, with a focus on its regulatory mechanisms involving the epithelial sodium channel (ENaC), the NF-κB signaling pathway, trophoblast cell apoptosis, and maternal-fetal blood vessel formation. We also prospect the potential of SGK1 as a therapeutic target for pregnancy-related disorders by modulating immune cell functions.