Role of B7-1 in Podocytes in Pathogenesis of Proteinuria

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DESCRIPTION (provided by applicant): Increasing evidence points to a critical role of podocytes in the initiation and progression of various glomerular diseases. We made the unexpected finding that under pathological conditions, with foot process effacement and proteinuria, podocytes express the molecule B7-1 (also termed CD80), a transmembrane protein expressed on the surface of B-cells and antigen presenting cells (APC). On B-cells and APC, B7-1 provides a costimulatory signal for T-cells through binding to its receptors CD28 and CTLA-4. The immune function of B7-1 has been well described. Much less is known about B7-1 expression and function in non-bone marrow derived cells. Here we provide evidence for a novel role of B7-1 in podocytes. Our preliminary data suggest that up regulation of B7-1 in podocytes contributes to the pathogenesis of proteinuria by altering glomerular permselectivity and provide a novel molecular target to tackle proteinuric kidney disease. Based on our observations, we propose a new working model/hypothesis: B7-1 expression by podocytes represents a pathogenic mechanism for disruption of the glomerular filtration apparatus. B7-1 may contribute to the pathogenesis of proteinuria in a dual fashion: i) by induction of foot process effacement and sequestration of vital SD molecules away from their normal sites of action, thereby altering glomerular permselectivity and ii) by modulating podocyte-matrix adhesion. We propose three Specific Aims to test our central hypothesis: Specific Aim 1 will elucidate the mechanism by which B7-1 orchestrates the reorganization of the podocyte actin cytoskeleton and SD complex. Specific Aim 2 will explore the role of B7-1 in podocyte adhesion to extracellular matrix. Specific Aim3 will establish the contribution of B7-1 expression in podocytes to the pathogenesis of proteinuric glomerular diseases. If our hypothesis is correct, the work proposed here will have broad significance in the long-term, because it will establish insight into the dynamics of the interaction between B7-1, foot process effacement, the actin cytoskeleton and the SD complex in nephrotic syndrome/FSGS. This should in the long-term enable us to develop novel, selective podocyte-protective therapies that tackle proteinuria and progression of glomerulosclerosis by blocking the activity of B7-1 in podocytes.