Plasma Extracellular Vesicles from Preeclamptic Patients Trigger a Detrimental Crosstalk Between Glomerular Endothelial Cells and Podocytes Involving Endothelin-1

TL;DR

This study shows that extracellular vesicles from preeclamptic patients harm kidney cells by triggering harmful interactions involving Endothelin-1.

Contribution

The study identifies a novel mechanism of glomerular damage in preeclampsia involving EVs and Endothelin-1-mediated crosstalk between kidney cells.

Findings

EVs from preeclamptic patients are higher in concentration and size compared to healthy controls.

PE-EVs induce kidney cell damage by increasing ROS and albumin permeability.

Endothelin-1 released by endothelial cells downregulates nephrin in podocytes, contributing to proteinuria.

Abstract

Extracellular vesicles (EVs) may play a role in preeclampsia (PE)-associated glomerular damage. We herein investigated the role of PE plasma EVs in triggering a detrimental crosstalk between glomerular endothelial cells (GEC) and podocytes (PODO). Clinical and laboratory variables were examined at T0 (diagnosis), T1 (delivery), and T2 (one month after delivery) in 36 PE patients and 17 age-matched controls. NanoSight and MACSPlex evaluated EV concentration, size, and phenotype. GEC and PODO were stimulated with plasma EVs to study viability, reactive oxygen species (ROS) production, permeability to albumin, endothelial-to-mesenchymal transition, and Endothelin-1 release. EV size and concentration were higher in PE than in healthy controls and in severe than in mild forms of disease. At T0, higher EV concentration correlated with proteinuria, blood pressure, uric acid, and liver enzyme levels. PE-EVs originated from leukocytes, endothelial cells, platelets, and the placenta and induced GEC and PODO damage as shown by the reduction of viability, increased ROS release, and albumin permeability. Co-culture experiments demonstrated that PE-EVs mediated a deleterious intraglomerular crosstalk through Endothelin-1 release from GEC able to down-regulate nephrin in PODO. In conclusion, we observed in PE plasma a peculiar pattern of EVs able to affect GEC and PODO functions and to induce proteinuria through Endothelin-1 involvement.

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