Glomerular capillary hypertension appears to play an important role in the progression of renal disease. Elevations in the mean glomerular transmembrane pressure difference () are associated with the development of proteinuria and glomerular sclerosis in a variety of experimental models of progressive renal disease, and normalization of in rats has been shown to provide structural protection and to preserve filtration capacity and selectivity.
The first aim of the proposed research is to elucidate the physical factors underlying the effects of on barrier function, including changes in glomerular pore-size distribution and membrane fixed charge.
The second aim i s to develop and verify methods for using the clearances of exogenous tracer macromolecules to estimate . Fractional clearances of dextran, ficoll, and dextran sulfate will be measured in normal rats and in rats with various forms of glomerular injury, following chronic or acute alterations in . Micropuncture measurements of glomerular hemodynamic variables in the same animals will permit the precise characterization of pressure-induced changes in membrane properties, and will allow a direct comparison with values of estimated using dextran sieving data. Theoretical models will be developed which provide more realistic descriptions of the dextran probes and of the glomerular barrier than are presently available. Application of these models to the micropuncture and clearance data will make it possible to assess for the first time the relative contributions of size-and-charge-related defects to the albuminuria that accompanies glomerular hypertension. Use of these models to define the optimal approach for calculating from dextran sieving data in rats will contribute to the long-term objective (beyond the scope of this proposal) of developing a noninvasive methodology for estimating in humans, for whom there is presently no method to monitor the effects of disease or therapy on .

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK041641-03
Application #
2141848
Study Section
General Medicine B Study Section (GMB)
Project Start
1991-07-01
Project End
1995-05-31
Budget Start
1993-06-01
Budget End
1995-05-31
Support Year
3
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Massachusetts Institute of Technology
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
City
Cambridge
State
MA
Country
United States
Zip Code
02139
Edwards, A; Deen, W M (1995) Error propagation in the estimation of glomerular pressure from macromolecule sieving data. Am J Physiol 268:F736-45
Oliver 3rd, J D; Simons, J L; Troy, J L et al. (1994) Proteinuria and impaired glomerular permselectivity in uninephrectomized fawn-hooded rats. Am J Physiol 267:F917-25
Oliver 3rd, J D; Anderson, S; Troy, J L et al. (1992) Determination of glomerular size-selectivity in the normal rat with Ficoll. J Am Soc Nephrol 3:214-28