Excess release of reactive oxygen species (ROS) is a major cause of oxidative stress. This disturbance has been implicated as a cause of preeclampsia, a pregnancy-related disorder characterized by hypertension and proteinuria. Increased oxidative stress leads to trophoblast apoptosis/necrosis and alters the balance between pro- and anti-angiogenic factors, resulting in generalized maternal endothelial dysfunction. Trials using antioxidants have significantly failed to improve the condition of, or in any way protect, the mother from the life-threatening complications of this syndrome. Nuclear factor-erythroid 2-related factor 2 (Nrf2) is a potent transcription activator that regulates the expression of a multitude of genes that encode detoxification enzymes and anti-oxidative proteins. Recent discussion on evidence of a link between Nrf2 and vascular angiogenic balance has focussed on the downstream target protein, heme oxygenase-1 (HO-1). HO-1 metabolizes heme to biliverdin, iron and carbon monoxide (CO). HO-1/CO protects against hypertensive cardiovascular disease and contributes to the sustained health of the vascular system. In one animal model, sFlt-1 (soluble fms-like tyrosine kinase-1) has induced blood pressure elevation, but the induction of HO-1 attenuated the hypertensive response in the pregnant animals. The special conditions under which Nrf2 participates in the pathogenesis of preeclampsia are still unclear, as is whether Nrf2 attenuates or stimulates the processes involved in this syndrome. In this review, we summarize recent theories about how Nrf2 is involved in the pathogenesis of preeclampsia and present the reasons for considering Nrf2 as a therapeutic target for the treatment of preeclampsia.

A possible protective role of Nrf2 in preeclampsia

Preeclampsia is a multi-system hypertensive disorder of pregnancy, with significant rates of maternal and neonatal morbidity. It represents a major cause of preterm birth, as definitive treatment demands fetal delivery. Although its pathophysiology is complicated, placental hypoxia and endothelial dysfunction constitute established pathogenetic steps of the disease. Inflammation is considered to be a crucial mediator of preeclampsia process, as an imbalance between TH 1, TH 2, and TH 17 immune responses is observed. The present review accumulates current knowledge about the contribution of interleukins in preeclampsia, summarizing the pathways through which each interleukin exerts its function in the disease. Also, the role of genetic polymorphisms is explored and the predictive efficacy of maternal serum interleukin levels is evaluated. Finally, recommendations about the safe interpretation of the outcomes, as well as guidance for future research, are provided.

The role of interleukins in preeclampsia: A comprehensive review.

To perform serum microRNA expression profiling to identify members of chromosome 19 miRNA cluster involved in preeclampsia development. Serum chromosome 19 miRNA cluster microRNA expression profiling was evaluated at 12, 16, and 20 gestational weeks and at the time of preeclampsia diagnosis, in women who developed preeclampsia (WWD-PE; n = 16) and controls (n = 18) using TaqMan low density array plates. A total of 51 chromosome 19 microRNA cluster members were evaluated. The circulating hsa-miRs 512-3p, 518f-3p, 520c-3p, and 520d-3p, were differentially expressed between groups (P < 0.05). Compared with controls, serum levels of hsa-miR-518f-3p at 20 GW were useful for identifying WWD-Mild-PE (P = 0.035) and WWD-Severe-PE (P = 0.007). Serum hsa-miRs 512-3p, 518f-3p, 520c-3p, and 520d-3p, are differentially expressed between WWD-PE and controls and their role in the development of preeclampsia should be investigated further.

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Circulating levels of specific members of chromosome 19 microRNA cluster are associated with preeclampsia development

The molecular mechanism that leads to pregnancy-induced hypertension (PIH), a pregnancy-specific syndrome, remains poorly understood. It has been suggested that microRNAs (miRNAs) may be potentially useful biomarkers for severe preeclampsia (PE), which is an important condition associated with PIH. The aim of the present study was to identify miR-204 by verifying differentially expressed serum miRNAs in patients with PIH during pregnancy compared with normal controls. Subsequently, the effects of miR-204 on proliferation and apoptosis of human choriocarcinoma (JAR) cells in hypoxic microenvironment were investigated. Previous studies indicated a number of miRNA candidates and the present study validated the expression of eight miRNAs in serum samples using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). A higher expression of miR-204 was identified in patients with PIH. To assess the impact of miR-204 inhibition on hypoxic JAR cells function in vitro, cell proliferation was detected using a Cell Counting Kit-8 assay. The rate of apoptosis and cell cycle progression was then examined by flow cytometry. RT-qPCR confirmed that serum miR-204-5p is more highly expressed in patients with PIH. Further statistical analysis indicated that the survival ratio of JAR cells in hypoxic microenvironments was increased in the miR-204-5p inhibitor group. However, the miR-204-5p inhibitor protected hypoxic JAR cells from apoptosis. The analysis of cell-cycle status demonstrated that the percentage of cells in the G2/G1 phase was larger compared with the control group. The results of the present study suggest that low levels of miR-204-5p may increase cell proliferation and reduce cell apoptosis with cell cycle changes in vitro. Therefore, serum miR-204-5p may be used as a notable biomarker for the diagnosis, prevention and treatment of PIH.

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An exploratory study into the role of miR-204-5p in pregnancy-induced hypertension

Background: Preeclampsia, a pregnancy disorder characterized by hypertension and proteinuria, represents the leading cause of fetal and maternal morbidity and mortality in developing countries. The...

Early pregnancy protein multiplex screening reflects circulating and urinary divergences associated with the development of preeclampsia.

Objective: To evaluate the peripheral blood mononuclear cell (PBMC) expression levels of hemeoxygenase 1 (HMOX-1), superoxide dismutase 1 (SOD-1), vascular endothelial growth factor A (VEGF-A), transforming growth factor beta 1 (TGF-β1), interleukin (IL)-6, IL-15 and AdipoQ genes to study their association with preeclampsia (PE). Methods: A total of 177 pregnant women were recruited: 108 cases and 69 controls. Quantification of gene expression was measured by quantitative real-time polymerase chain reaction (PCR) using TaqMan probes. Results: Underexpression of VEGF-A and TGF-β1 was a constant in most of the cases (80.91% and 76.36%, respectively) and their expression was associated with onset and/or severity of disease (p values < 0.05). IL-6, IL-15 and AdipoQ, showed low or no expression in PBMC samples evaluated. Conclusion: PBMC underexpression of VEGF-A and TGF-β1 is a hallmark of PE in the study population.

G. G. Guerrero

Papers

Expression levels of seven candidate genes in human peripheral blood mononuclear cells and their association with preeclampsia.