MODULATION OF GLOMERULAR HYDRAULIC PERMEABILITY

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The long term goal of the proposed studies is to gain understanding of the factors that modulate glomerular hydraulic permeability and ultimately limit glomerular filtration rate in normal glomeruli and in renal disease. Glomerular filtration proceeds by an extracellular pathway that traverses endothelial cell fenestrae, the biochemically complex basement membrane, and the specialized slit-pore junctions between adjacent glomerular podocytes. The ultrafiltration coefficient, Kf or LpA, is the product of the hydraulic conductivity of the capillary wall and the filtration area and is an important determinant of single nephron filtration rate. Filtration will be induced in vitro using isolated glomeruli and Kf will be estimated from the initial rate of filtration after application of a known gradient. Studies will be conducted to address the following hypotheses. 1) Lp is nearly constant in adult mammalian glomeruli; Lp is higher in glomeruli in the neonatal period and during intravascular volume expansion and is diminished during volume depletion and in chronic renal failure. 2) Elevated Lp in the neonatal period is consequent to immaturity of podocytes; maturation is induced by the effects of glucocorticoids. 3) Altered Lp during volume depletion and expansion is the result of secondary cellular changes caused by altered perfusion rate and pressure rather than by direct effects of vasoactive substances. 4) Diminished Lp following subtotal nephrectomy also results from changes in the cellular component of the filtration pathway rather than from loss of filtering area; normal Lp may be restored by dietary manipulations or other interventions that return glomerular perfusion parameters toward normal. 5) Lp is modulated by changes in the filtration pathway at the epithelial slit-pore; these alterations may be documented in pathologic material as well as after experimental manipulations that change podocyte cell volume, cytoskeleton or intercellular junctions.