Progression to ESRD of diabetic glomerulosclerosis and other sclerosing glomerular diseases (e.g. FSGS) is associated with a leak of protein through the glomerular filter (the Nephrotic Syndrome). A major cell responsible for maintaining the integrity of the glomerular filter is the podocyte, whose interdigitating foot processes about the glomerular basement membrane, and between which the glomerular filtrate is formed. With prior support from the Renal Center we have identified, cloned and sequenced two major proteins of importance for the function of the glomerular filter. These are a novel podocyte foot process receptor tyrosine phosphatase (called GLEPP1) and podocalyxin (the major negatively charged molecule of the foot process originally identified by Farquhar and colleagues which is responsible for keeping foot processes apart by charge repulsion). Recent analysis of the GLEPP1 receptor shows that antibodies to the GLEPP1 receptor-like PTPase cause the glomerulus to become more permeable to albumin (leaky), probably in part by inhibiting the PTPase function of the enzyme. Thus a direct and previous unknown mechanism of control of the glomerular filter has been identified. At the same time new information shows that in other cells PTPases regulate intercellular junctions that are analogous to the slit diaphragms (specialized intercellular junctions) that serve as filtration devices between the foot processes of the podocyte. In this application we propose (a) to identify the GLEPP1 ligand using a recombinant GLEPP1 extracellular domain construct and a mammalian cDNA expression cloning strategy, and (b) to test the hypothesis that interference with the GLEPP1-ligand interaction modulates glomerular filter permeability using an isolated glomerular permeability assay. The long term goal will be to develop pharmacologic agents which can modulate glomerular permeability through this mechanism.
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