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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK022040-10
Application #
3227197
Study Section
General Medicine B Study Section (GMB)
Project Start
1978-07-01
Project End
1990-03-31
Budget Start
1988-04-01
Budget End
1990-03-31
Support Year
10
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Kansas
Department
Type
Schools of Medicine
DUNS #
016060860
City
Kansas City
State
KS
Country
United States
Zip Code
66160
Sharma, R; Sharma, M; Li, J Z et al. (1997) Direct effects of platelet-activating factor on glomerular capillary permeability. Kidney Blood Press Res 20:25-30
Adler, S; Sharma, R; Savin, V J et al. (1996) Alteration of glomerular permeability to macromolecules induced by cross-linking of beta 1 integrin receptors. Am J Pathol 149:987-96
Sharma, R; Savin, V J (1996) Cyclosporine prevents the increase in glomerular albumin permeability caused by serum from patients with focal segmental glomerular sclerosis. Transplantation 61:381-3
Savin, V J; Sharma, R; Sharma, M et al. (1996) Circulating factor associated with increased glomerular permeability to albumin in recurrent focal segmental glomerulosclerosis. N Engl J Med 334:878-83
Savin, V J; Johnson, R J; Couser, W G (1994) C5b-9 increases albumin permeability of isolated glomeruli in vitro. Kidney Int 46:382-7
Savin, V J (1993) Mechanisms of proteinuria in noninflammatory glomerular diseases. Am J Kidney Dis 21:347-62
Dileepan, K N; Sharma, R; Stechschulte, D J et al. (1993) Effect of superoxide exposure on albumin permeability of isolated rat glomeruli. J Lab Clin Med 121:797-804
Wiegmann, T B; Sharma, R; Diederich, D A et al. (1990) In vitro effects of cyclosporine on glomerular function. Am J Med Sci 299:149-52