DCAF13 is essential for the pathogenesis of preeclampsia through its involvement in endometrial decidualization.

Preeclampsia (PE) is a syndrome that occurs during pregnancy and affects more than 8 million mother-infant pairs each year. Most previous studies on the pathogenesis of PE have focused on the placenta. However, decidualization is the basis for placentation and subsequent development. The CRL4 (Cullin 4-RING E3 ubiquitin ligase) complex ubiquitinates and degrades substrates, while DCAF13 (DDB1 and CUL4-associated factor 13) is a component and substrate receptor of this complex, which recognizes and recruits the complex different substrates. DCAF13 plays a major role in the maintenance of follicles and the development of oocytes. However, its role in subsequent pregnancies remains unclear. In the present study, we first investigated DCAF13 levels in the decidua of PE patients and found that it is significantly lower than that of normal pregnant women. Second, we found that DCAF13 expression increases during decidualization, and reducing expression of DCAF13 by siRNA prevents decidualization. Third, in vivo experiments in mice further revealed that Dcaf13 expression increases with decidualization. Finally, we generated and found that uteri of pseudopregnant conditional Dcaf13 knockout mice fails to undergo decidualization. Therefore, we propose that DCAF13 plays a key role in decidualization. Abnormal expression of DCAF13 affects the decidualization process, which is likely involved in the occurrence and development of PE.

Dysregulated GLUT1 may be involved in the pathogenesis of preeclampsia by impairing decidualization.

Preeclampsia (PE), a hypertensive complication in pregnancy, is a major contributor to maternal and fetal morbidity and mortality. PE has long been regarded a heterogeneous disorder with a pathogenesis that involves multiple genes and factors. Glucose transporter 1 (GLUT1) is a central rate-limiting pump that is involved in glucose uptake and subsequent utilization. Our previous RNA-seq results demonstrated GLUT1 was significantly downregulated in deciduas from patients with severe PE. Therefore, in this study, we aimed to explore the role of GLUT1 in the occurrence of PE. Our data showed that mRNA and protein levels of GLUT1 were significantly downregulated in the deciduas from patients with severe PE. Additionally, GLUT1 levels were substantially upregulated in human endometrial stromal cells (HESCs) during in vitro decidualization. Moreover, GLUT1 knockdown significantly reduced the mRNA levels of decidualization markers (IGFBP1 and PRL) and aerobic glycolysis-related genes (LDHA and MCT4), as well as decreased glucose uptake and lactate production. Furthermore, upon GLUT1 knockdown, the levels of apoptotic genes P53, P21, and BAX increased whereas the level of BCL2 decreased. Target prediction results and luciferase analysis showed that GLUT1 is one of the targets of miR-140-5p, which is partly responsible for downregulated GLUT1 levels. Collectively, these results demonstrate that GLUT1 exerts a pivotal role in human decidualization by participating in glycolysis, and that GLUT1 deficiency may trigger aberrant glycolysis, thereby leading to destructive decidualization that may impede blastocyst implantation, trophoblast invasion, and subsequent placental development, which are associated with PE. Taken together, these data suggest that GLUT1 might be a promising target for PE therapy.

Dysfunction of Decidual Macrophages Is a Potential Risk Factor in the Occurrence of Preeclampsia.

Preeclampsia is a multi-factorial and multi-genetic disorder that affects more than eight million mother and baby pairs each year. Currently, most of the attention to the pathogenesis of preeclampsia has been focused on placenta, but recent progresses suggest that excellent decidualization lays foundation for placentation and growth. Moreover, preeclampsia is associated with an imbalance in immunoregulatory mechanisms, however, how the immune regulatory system in the decidua affects preeclampsia is still unclear. In our study, after intersecting the genes of differentially expressed between preeclampsia and the control gotten by conventional expression profile analysis and the genes contained in the ligand receptor network, we found eight differentially expressed genes in a ligand-receptor relationship, and the eight genes have a characteristic: most of them participate in the interaction between decidual macrophages and other decidual immune cells. The results of single-cell sequencing of decidual cells further demonstrated that decidual macrophages affect the functions of other immune cells through export. As a result, abnormal gene expression affects the export function of decidual macrophages, which in turn affects the interaction of decidual macrophages with other immune cells, thereby destroying the original immune regulation mechanism, and ultimately leading to the occurrence of preeclampsia.