Evidence For Endothelial Involvement in Idiopathic Nephrotic Syndrome: A Role for CD93

Project Summary/Abstract: Idiopathic Nephrotic Syndrome (INS) is the most common type of nephrotic syndrome in childhood, yet its cause remains unknown. Most authorities consider the disease to be mediated by an unknown circulating factor that directly binds the podocyte, causing podocyte activation and proteinuria. However, our group has shown that the disease may not be that simple and that there is also injury to the glomerular endothelial cells (GEnC) that line the inside of the capillary. We recently showed evidence of circulating endothelial biomarkers in ~90% of INS patients. In preliminary studies, we found that one specific endothelial protein, CD93, was especially important, which may relate to its ability to activate focal adhesion kinase (FAK), a protein that is activated in INS and causes podocyte injury. We found high CD93 expression in GEnC from kidney biopsies of INS patients and that levels of its soluble form were high in serum and urine in ~90% of ~300 patients. We also found that sera in relapse stimulate cultured GEnC to release CD93; and importantly, that activation of podocytes by relapsing sera could be blocked with an antibody to CD93. Our preliminary work also identifies urinary CD93 as predictor of kidney disease progression. Our data suggest that the pathogenesis of INS involves an intermediary step of GEnC activation that facilitates podocyte injury. Our central hypothesis is that circulating factors activate GEnC to release the soluble form of CD93, which, in turn, acts as (1) a predictive biomarker for kidney disease progression, and (2) mediator of podocyte activation via FAK signaling. In aim 1, we will study whether CD93, in glomeruli, urine or serum, predicts clinical outcomes and associates with structural and/or biological changes affecting glomeruli. This will be complemented by pilot studies to delineate the patterns of soluble CD93 across disease states, and its specificity across glomerular diseases. In aim 2, we will combine multiple in vitro approaches to identify the source of soluble CD93 and its effects on human podocytes. In aim 3, we will study the CD93 involvement in 2 classic animal models of INS (puromycin and adriamycin), and whether CD93 blockade prevents and/or mitigates proteinuria. Our hypothesis is innovative because GEnC are not considered to have an important role in INS. The combination of several approaches to assess endothelial injury and the inclusion of a large population provide rigor to the clinical studies. Integrating multiple cell systems and classic models of INS also provide a rigorous approach to test causality. Our proposal is highly translational and could lead to the identification of a novel prognostic and therapeutic target in INS. A four-year mentored career development plan has also been devised, which incorporates training in endothelial biology, precision medicine, and leadership by an experienced mentoring and advisory teams. The candidate’s long-term career goal is to become an independent investigator discovering biomarkers, mechanistic pathways, and targeted therapies in INS.