CELLULAR DETERMINANTS OF GLOMERULAR PERMSELECTIVITY

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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. I propose to test the hypothesis that hormones which influence glomerular function in vivo do so by their action on cells of the glomerular filtration barrier and that intracellular processes such as calcium flux and polymerization of the actin cytoskeleton are potential mechanisms by which these cells might regulate permeability. I will utilize two in vitro techniques developed in my sponsor's laboratory which facilitate direct assessment of the glomerular filtration barrier, independently of potentially confounding variables present in vivo, such as local and systemic hormones and hemodynamics. In addition, I will use confocal microscopy to assess the importance of two potential intracellular mediators of permeability, intracellular calcium flux and polymerization of the actin cytoskeleton in discrete mesangial and epithelial cells in thin optical cross sections of intact, living glomeruli. Specifically, I will address the following questions: I.Do Angiotensin II and IGF-1, systemic factors which influence glomerular function, have a direct effect on the glomerular permeability barrier? II.Do intracellular calcium and the actin cytoskeleton modulate glomerular permeability?