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Author Spotlight: Modeling an Aspect of Preeclampsia in Female Mice Using Hypoxic Human Placenta-Derived Small Extracellular Vesicles
Published on: January 26, 2024
Dysregulated GLUT1 may be involved in the pathogenesis of preeclampsia by impairing decidualization
Man Yang1, Hua Li2, Miaomiao Rong1
1Shandong Provincial Key Laboratory of Animal Resistance Biology, College of Life Science, Shandong Normal University, Ji'nan, 250014, Shandong, China.
Insights
Glucose transporter 1 (GLUT1) deficiency impairs decidualization, potentially contributing to preeclampsia (PE). GLUT1 plays a key role in glycolysis and is crucial for healthy pregnancy outcomes, suggesting it as a therapeutic target for PE.
Area of Science:
- Reproductive biology and molecular genetics
- Obstetrics and gynecology
- Metabolic disorders
Background:
- Preeclampsia (PE) is a major cause of pregnancy complications, involving complex genetic and environmental factors.
- Glucose transporter 1 (GLUT1) is vital for glucose metabolism, and its downregulation was previously observed in severe PE deciduas.
- The precise role of GLUT1 in the pathogenesis of PE remains to be fully elucidated.
Purpose of the Study:
- To investigate the role of GLUT1 in human decidualization and its potential contribution to preeclampsia.
- To explore the regulatory mechanisms of GLUT1 expression during decidualization.
- To assess the impact of GLUT1 deficiency on decidual cell function and viability.
Main Methods:
- Quantitative analysis of GLUT1 mRNA and protein levels in deciduas from severe PE patients and in vitro decidualized human endometrial stromal cells (HESCs).
- GLUT1 knockdown in HESCs to assess effects on decidualization markers, glycolysis-related genes, glucose uptake, lactate production, and apoptosis.
- Bioinformatic prediction and luciferase assays to identify regulatory miRNAs targeting GLUT1.
Main Results:
- GLUT1 mRNA and protein were significantly downregulated in deciduas from severe PE patients and upregulated during in vitro decidualization.
- GLUT1 knockdown reduced decidualization markers (IGFBP1, PRL), glycolysis genes (LDHA, MCT4), glucose uptake, and lactate production.
- GLUT1 knockdown increased apoptosis (P53, P21, BAX) and decreased anti-apoptotic gene (BCL2) expression, identifying miR-140-5p as a regulator.
Conclusions:
- GLUT1 is essential for human decidualization, regulating glycolysis and maintaining cellular function.
- GLUT1 deficiency disrupts decidualization, potentially leading to implantation and placental development issues associated with PE.
- GLUT1 represents a potential therapeutic target for managing preeclampsia.
Abstract:
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.
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