Epithelial Cell Detachment in the Nephrotic Glomerulus: A Receptor Co-operativity Model

Detachment of epithelial cells from the glomerular capillary wall correlates with the massive increase in protein leakage across the capillary wall that is characteristic of many renal diseases. We introduce the hypothesis that this detachment process involves three classes of physical events acting at the subcellular level: the receptor-mediated binding of epithelial cells to basement membrane, the transglomerular hydraulic pressure gradient acting to lift the cells off the basement membrane, and a receptor-receptor co-operativity induced by mechanical deformations of the epithelial cell surface. After presenting the available evidence, we explore the hypothesis by means of a simplified, quantitative model of the detachment process. The model is developed by mapping between the stochastic events of cell adhesion receptor binding and the equilibrium statistical mechanics of the Ising model. Monte Carlo simulations predict cell attachment under normal conditions, as expected from experimental data, and detachment at lower receptor binding affinity and/or increased pressure gradient. The normal attached state in the model is found to be particularly sensitive to changes in the receptor-binding affinity. The amount of resistance the cell surface offers to deformation forces is a key determinant of whether the detachment of small clusters of receptors spreads to involve large areas of the plasma membrane, precipitating bulk detachment.