UC San Diego

Preeclampsia (PE) and Hemolysis, Elevated Liver Enzymes and Low Platelet Syndrome (HELLP), are two high-risk pregnancy complications believed to be due to placental dysfunction. PE is a hypertensive pregnancy complication that is the leading cause of perinatal and maternal death in the U.S., while HELLP is a pregnancy-related blood and liver disease. Patients diagnosed with severe PE are often diagnosed with HELLP as well. Although HELLP is less common than PE, it has a strikingly high mortality rate of 25%. Little is known as to how their molecular characteristics overlap and differ from one another. Here, we use a molecular approach at detecting microRNA (miRNA) biomarkers specific for PE and HELLP in extracellular vesicles (EV). miRNAs play a role in many diseases as they are noncoding RNA that can alter gene expression by binding to sequences of mRNA, ultimately degrading it. EVs bud off from all tissue types and circulate through biofluids, facilitating cell-cell communication, thus our goal is to look for extracellular RNA, including RNA from EVs, in biofluids to see if PE and HELLP have different miRNA levels compared to healthy pregnancies (Conceptual Figure 1). Through analysis of sequenced miRNAs, we found that the miRNA content of urinary EVs differs between pregnancy groups. The miRNA, miR-122-5p, appears to be found in both urinary EVs (isolated with mirVana) and serum EVs. This specific miRNA is found at high levels in HELLP samples compared to Normal and PE. Upon further investigation, hsa-miR-122-5p is involved in trophoblast proliferation/differentiation, where it inhibits the cell cycle by targeting CDK4 expression. The highly expressed miRNAs in HELLP and PE: miR-122-5p, miR-1246, miR-27b-3p, miR-22-3p miR-514a-3p, miR-99a-5p (HELLP and PE), and miR-486-5p (just PE) all play roles in the differentiation and proliferation of placental cells (trophoblast and endothelial cells). Our results suggest molecular mechanisms behind the development of PE and HELLP, and propose a minimally invasive diagnostic approach for PE and HELLP.