IGF2BP1 Enhances Neprilysin mRNA Stability to Promote Proliferation, Invasion, and Angiogenesis in Placental Trophoblasts.

BACKGROUND AND OBJECTIVE: Preeclampsia (PE) is a severe gestational disorder characterized by sudden hypertension and proteinuria, with substantial risks to both mother and fetus. This study aims to delineate the role of neprilysin, a metalloprotease known for its role in modulating vasoactive peptides, in the pathophysiology of PE. METHODS: We recruited a cohort of 57 participants, comprising 38 patients diagnosed with PE and 19 healthy controls, matched for demographic and clinical characteristics. Neprilysin expression was assessed in serum and placental tissues through quantitative RT-qPCR and Western blot analyses. Functional impacts of neprilysin modulation were explored via siRNA knockdown and overexpression in HTR8/SVneo cells, followed by assessments of oxidative stress, mitochondrial function, apoptosis, and trophoblast invasion using various biochemical assays including CCK-8, DCFH-DA, JC-1 staining, and flow cytometry. RESULTS: Our results demonstrate a marked overexpression of neprilysin in the serum and placental tissues of PE patients compared to healthy controls. Elevated neprilysin levels were positively correlated with increased systolic and diastolic blood pressures. In functional assays, neprilysin knockdown alleviated H(2)O(2)-induced oxidative stress, restored mitochondrial function, and improved cell invasion and migration in EVT cells. Conversely, the overexpression of IGF2BP1, a regulator of mRNA stability, exacerbated neprilysin expression and intensified cellular damage under oxidative stress conditions. The reciprocal regulation of neprilysin by IGF2BP1 highlights a critical molecular interplay impacting cellular resilience to oxidative stress in PE. CONCLUSION: These findings establish neprilysin as a critical mediator in the pathogenesis of PE, where its aberrant overexpression is linked to exacerbated hypertensive symptoms and impaired trophoblast function. The interaction between neprilysin and IGF2BP1 provides a potential therapeutic target for mitigating the progression of PE, suggesting avenues for future intervention strategies.