Permeability of the glomerular filtration barrier in relation to the size, shape, charge and deformability of the permeating molecules
Sammanfattning: Characterization of the glomerular filtration barrier is of fundamental importance for understanding the pathophysiology of proteinuric kidney diseases. Furthermore, it can be of key value in the understanding of microalbuminuria, which is often associated with endothelial dysfunction in conjunction with cardiovascular disease. In the four studies of this doctoral thesis, macromolecular probes having different frictional ratios (f/f0) and charge were investigated in order to give deepened insights into the usefulness of polysaccharides as probes of the permselectivity of the glomerular filter for proteins. In Study I, the extensively cross-linked polysaccharide Ficoll, was shown to overestimate the true permeability of the glomerular filtration barrier to neutral globular proteins, indicating that size-selectivity is even more important than previously recognized. However, Ficolls in the SE-radius range 55-75Å, were not hyperpermeable across the large pores of the glomerular filter, indicating their usefulness for studying proteinuric diseases. In study II, the results of recent publications, indicating the lack of charge-selectivity in the glomerular filter, were shown to be artifactual. Thus, polysaccharides, when negatively charged, seemed to become expanded and to increase their f/f0, thereby becoming more hyperpermeable. Thus earlier findings, showing that the glomerular filter discriminates proteins based on charge, are still valid. In study III, we showed that the main size-restrictive barrier of the glomerular filter lies, not at the podocyte level, but closer to the plasma compartment, or may be evenly distributed along the thickness of the filter. This was indicated by the lack of concentration-polarization upon increasing GFR. Study IV demonstrated that the differential permeabilities of polysaccharides and proteins across the glomerular barrier were not observed across the continuous capillary walls of the peritoneal membrane, an enigma that warrants further study.
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