A Mathematical Model for Nephrin Localization in Podocyte Foot Processes

Abstract

The first stage of blood filtration occurs in the glomerulus, where water and other small sized molecules are freely filtered into the urinary space while albumin and larger proteins are retained in the blood capillaries. Maintenance of the size-selective glomerular filtration barrier is regulated by highly differentiated cells, podocytes, their cell-cell interactions in the slit diaphragm (SD) and the cell-GBM (glomerular basement membrane) interaction of the podocyte foot processes. The central component of the SD is the transmembrane protein nephrin. Proper spatial localization of nephrin to the SD is an essential step in embryonic development and injury recovery. Mutations that affect nephrin interaction kinetics disrupt the cell and filter morphologies and result in phenotypes that range from mild to lethal. A major deficiency in addressing podocyte disease is the lack of a quantitative model of signaling with correct morphology and protein distribution. We developed a mathematical model in order to assess the contributions of nephrin trans-dimerization, targeting to lipid rafts and interaction with intracellular proteins (such as tight and adherent junction proteins and podocin) and actin dynamics within the foot processes at the SD. We use rule-based modeling to account for multiple complexes and phosphoforms and investigate protein localization and signaling on the level of domain-domain interactions. Using the Virtual Cell software,the model is associated with the spatial organization of the foot processes, incorporating geometry effects. (supported by NIH grants TRO1DK087650 and P41RR013186)