Preeclampsia serum induces human glomerular vascular endothelial cell hyperpermeability via the HMGB1-Caveolin-1 pathway.

Highlights • New cognition on GEC barrier dysfunction and proteinuria development of severe PE patients. • A model of GEC monolayer in vitro was used to attempt to illustrate how PE serum affect GEC monolayer permeability. • New ideas on therapeutic target for expectant treatment of early-onset PE patients with massive proteinuria. Abstract To explore new ideas about the pathogeny of preeclampsia (PE) proteinuria, this study focused on whether severe PE serum (PES) could induce high-molecular-weight protein (HMWP) hyperpermeability in glomerular endothelial cells (GEC) via the HMGB1-Caveolin-1 (CAV-1) pathway. Normal pregnancy serum (NPS) and severe PES were used to treat primary human GEC monolayer for 24 h. The CAV-1 inhibitor methyl-beta-cyclodextrin (MBCD), the HMGB1 inhibitor glycyrrhizicacid (GA), recombinant HMGB1 (rHMGB1) were also used to treat GEC monolayer that were stimulated by NPS or severe PES. The dynamic permeability of GEC to HMWP was detected by Evans blue-labeled BSA and CAV-1 expression in GEC was analyzed by immunofluorescence staining and Western blotting. We detected HMGB1 expression in placenta and serum in normal pregnancy and severe PE. The results showed that severe PES significantly promoted GEC hyperpermeability and CAV-1 expression. By inhibiting CAV-1 expression, MBCD reversed severe PES-induced GEC monolayer permeability. HMGB1 expression in PE placenta and serum was significantly increased. Compared with that in normal placenta, HMGB1expression was increased in the cytoplasm of syncytiotrophoblast cells in PE placenta. GA decreased the severe PES-induced hyperpermeability and CAV-1 expression in GEC. rHMGB1 induced high expression levels of CAV-1 and HMWP hyperpermeability in GEC. In conclusion, HMGB1 is increased in severe PE patients and induces the expression of CAV-1 in GEC. High expression of CAV-1 in GEC can promote HMWP hyperpermeability, which may contribute to the development of PE proteinuria. [ABSTRACT FROM AUTHOR]