STRUCTURAL DETERMINANTS OF GLOMERULAR PERMEABILITY

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The glomerulus is a complex filter with remarkably high hydraulic conductivity and low macromolecular permeability. Abnormalities of hydraulic conductivity and macromolecular permeability accompany most types of progressive renal disease, yet the understanding of the physiology and regulation of the glomerular permeability barrier is not well developed, probably due in part to the lack of models where glomerular function can be assessed independently of the hemodynamic and hormonal factors which contribute importantly, but not solely, to the permeance of water and macromolecules across the glomerular capillary wall. The development of two in vitro models of glomerular permeability whereby the contribution of discrete components of the glomerular capillary wall to the maintenance and regulation of permeability can be analyzed. The filtration properties of layered, intact glomeruli will be assessed in a filtration cell while the filtration across single, intact, glomerular capillary loops will be examined by confocal microscopy. In addition, confocal microscopy facilitates the investigation of intracellular calcium flux and the actin cytoskeleton, mediators of permeability in other organs, in discrete cells within intact glomeruli. This proposal is designed to investigate the function of the glomerular permeability barrier with these two novel techniques, confocal microscopy and the filtration cell. The techniques will be further characterized and then utilized to develop and expand the available isoporous and fiber matrix models of glomerular macromolecule permeability. In addition, calcium flux and the actin cytoskeleton, likely intracellular mediators of permeability, will be examined in discrete cells in intact glomeruli with confocal microscopy to determine their role in the modulation of glomerular permeability. Finally, the resultant concepts about the glomerular permeability will be applied to two pathophysiologic models associated with acute alterations in the glomerular permeability barrier.