PHYSICO-CHEMICAL ASPECTS OF RENAL TRANSPORT PROCESSES

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The normal glomerular capillary wall is extremely permeable to water, and yet very effective at preventing the loss of plasma proteins into the glomerular ultrafiltrate. In the principal forms of kidney disease both of these aspects of glomerular function tend to be impaired: there is a reduced capacity for filtration of water, accompanied by less ability to selectively retain large molecules in plasma. The structural basis for normal or impaired glomerular permeability properties remains poorly understood. The overall objective of the proposed research is to develop theoretical models which will relate these functional properties to the physical characteristics of the structures that comprise the capillary wall, which include the fenestrated endothelium, glomerular basement membrane (GBM), and epithelial filtration slits with slit diaphragms. One specific aim is to characterize the movement of water and macromolecules across novel agarose-dextran gels that are designed as experimental models for the GBM. A second aim, also related to transport across the GBM, is to develop a theory to predict the effects of abundant solutes (such as the major plasma proteins) on the movement of tracers of varying size through gels or fibrous membranes. The results from these studies of GBM-like materials, together with improved hydrodynamic descriptions of macromolecule movement across the cellular parts of the barrier, lead to a third objective, which is to more accurately simulate filtration of water and uncharged macromolecules in the glomerulus as a whole. Additional aims are to apply the structure-based hydrodynamic models in collaborative studies of human glomerulopathies, and to extend them to describe intraglomerular signalling events that involve the movement of macromolecules between the glomerular epithelium and endothelium.