Recent studies published from the PI's laboratory show increased expression of Angiopoietin-like 4 (Angptl4) in podocytes in human and experimental glucocorticoid sensitive nephrotic syndrome. Secretion of this protein into the glomerular capillary loop leads to binding to the glomerular basement membrane (GBM), and results in the development of nephrotic range selective proteinuria, diffuse effacement of foot processes, and loss of GBM charge. Angptl4 secreted from podocytes in experimental minimal change disease (MCD) is deficient in sialic acid residues that would normally be incorporated at glycosylation sites. This hypo-salivated state, caused either by a relative deficiency of substrate or concomitant changes in the sialic acid biosynthetic pathway, influences the interaction of Angptl4 with GBM proteins. Feeding sialic acid precursor ManNAc to rats with transgenic expression of Angptl4 from podocytes over a period of 12 day results in over 40% reduction in albuminuria, and significantly increases sialylation of Angptl4. We hypothesize that podocyte secreted Angptl4 interacts with GBM proteins to induce proteinuria, and this process is strongly influenced by the state of Angptl4 sialylation.
In Specific Aim 1, we characterize the sialylation of podocyte secreted Angptl4 by studying its incorporation into N-glycans and / or O-glycans, and looking for changes in the sialic acid synthesis and incorporation pathway in experimental MCD.
In Specific Aim 2, we study the interaction of sialylated and hypo-sialylated Angptl4 with heparin sulfate proteoglycans using in vitro plate assays, and with all GBM proteins in tissue sections using the Proximity Ligation Assay.
In Specific Aim 3, we investigate the upregulation of podocyte Angptl4 expression in experimental MCD by transcriptional factor ZHX1, and propose experiments to study whether dominant negative ZHX1 constructs can be used to reduce Angptl4 expression in disease states. The experiments proposed in this application will help in the design of therapeutic strategies for the reduction of proteinuria.
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