Extracellular Vesicles as Mediators of Kidney Damage in Preeclampsia

Preeclampsia (PE) is a devastating hypertensive disorder of pregnancy and a leading cause of maternal and fetal mortality and morbidity worldwide. It affects 2-10% of women and accounts for 16% of maternal deaths related to childbirth in the United States. Maternal renal dysfunction is commonly associated with PE, characterized by glomerular endotheliosis and proteinuria, or appearance of protein in the urine. PE is a common cause of pregnancy-related acute kidney injury, and increases a woman’s risk of developing chronic renal, hypertensive, and cardiorenal disorders in the long term. Despite the renal manifestations of PE classically associated with this syndrome, little is known about the mechanisms of maternal kidney dam- age in PE. The placenta plays a key role in the development of PE, leading to widespread maternal endo- thelial dysfunction, hypertension, and systemic multi-organ failure in PE. Extracellular vesicles (EVs) containing RNA, protein, and lipid cargo are continuously released from the placenta directly into the ma- ternal peripheral circulation and interact with maternal organs including the kidney. Markers of proximal tubular injury are reportedly increased in severe preeclampsia, and GFP-positive placental EVs localize to the maternal proximal tubules in a mouse model. However, no studies have investigated the potential mech- anisms by which EVs from the placenta and maternal serum may interact with proximal tubules and other renal cell types, leading to kidney injury in PE. In the proposed research, we will utilize for the first time a novel, cutting-edge, validated 3D microfluidic human proximal tubule kidney-on-a-chip model (Emulate, inc.) engineered to mimic the proximal tubular lumen and peritubular vasculature to study the effects of placental and serum EVs from early and late-onset severe PE and normal pregnancy on renal cells. We will use a mouse model of EV-kidney interactions in pregnancy in tandem in order to dissect the functional effects of EVs from early and late-onset severe preeclampsia on maternal proximal tubules ex vivo. We will also investigate the effects of these EVs on the transcriptome of diverse renal cell populations including proximal tubular and glomerular cell types in this mouse model. Next Generation Sequencing techniques including bulk and single cell RNA-Seq will provide high-resolution molecular information on the effects of EVs on the maternal kidneys in PE. Relevance The only treatment option for PE remains removal of the placenta and delivery of the baby, often prema- turely. This research aims to understand the pathology of maternal kidney injury in PE in relation to EVs in pregnancy and will lead to the identification of novel molecular pathways and targets which could be ma- nipulated by therapeutics to reduce the acute and chronic renal effects of PE. Project Number: 1R01HD118111-01A1 | Fiscal Year: 2026 | NIH Institute/Center: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | Principal Investigator: Priyadarshini Pantham | Institution: UNIVERSITY OF CALIFORNIA, SAN DIEGO, LA JOLLA, CA | Award Amount: $600,016 | Activity Code: R01 | Study Section: Pregnancy and Neonatology Study Section[PN] View on NIH RePORTER: https://reporter.nih.gov/project-details/11298497