Induction of plasmalemmal vesicle-associated protein exacerbates glomerular endothelial injury in thrombotic microangiopathy.

Glomerular endothelial cell (GEnC) injury is a common feature across the wide spectrum of glomerular diseases. We recently reported that the endothelial-specific knockout of Krüppel-like factor 4 (Klf4) increases the susceptibility to GEnC injury and subsequent development of subacute thrombotic microangiopathy (TMA). However, the mechanism(s) mediating GEnCs response to injury in TMA are poorly understood. Single-nucleus RNA-sequencing demonstrated enrichment in pathways involved in angiogenesis, permeability, focal adhesion, dedifferentiation, and cytoskeletal organization in the endothelial cluster in mice with TMA. Plasmalemmal vesicle-associated protein (Plvap), a structural component of fenestral diaphragms, was highly enriched specifically in injured GEnCs. Induction of Plvap in cultured GEnCs increased proliferation, migration, and cell permeability with an accompanying loss of mature GEnC markers. Immunostaining for PLVAP in human kidney biopsies confirmed the increase in glomerular PLVAP in TMA, which correlated with a higher grade of glomerular injury. To date, this is the first study to show that the induction of Plvap in GEnCs shifts the cells to an immature state, which might exacerbate glomerular injury in TMA.NEW & NOTEWORTHY This study investigated the mechanism(s) underlying glomerular endothelial cell (GEnC) injury in thrombotic microangiopathy (TMA). We identified plasmalemmal vesicle-associated protein (PLVAP) as specifically upregulated in injured GEnCs in TMA, which was accompanied by pathways involved in angiogenesis and loss of differentiation. Induction of Plvap increased proliferation and migration of GEnCs. Human kidney biopsies with TMA demonstrated an increase in glomerular PLVAP, which correlated with histological markers of GEnC injury, confirming its pathologic role in TMA.