Focal glomerulosclerosis (FGS) is commonly seen in human and experimental models of renal disease. Characteristically, FGS is accompanied by proteinuria and a progressive decline in renal function. Although the pathogenesis of FGS has not been precisely illucidated, several non-immunologic factors have been implicated in the development of this lesion. It has been suggested that increased glomerular capillary pressures and flows may be fundamental to the development of FGS. Abnormalities in coagulation, renal prostaglandin metabolism and mesangial processing of phlogogenic macromolecules as well as glomerular epithelial cell damage may also participate in the pathogenesis of FGS. Recent studies from our laboratory have indicated that abnormal lipid metabolism may be a risk factor in the pathogenesis of FGS. We have demonstrated that two distinctly different lipid-lowering agents, clofibric acid and mevinolin, significantly ameliorated glomerular injury in rats with 5/6 nephrectomy and in obese Zucker rats. The results of these studies have led us to postulate that lipids are an important in the pathogenesis of FGS. Moreover, it is possible that a synergistic interaction between glomerular hypertension and hyperlipidemia could occur in the pathogenesis of FGS in a manner analogous to that observed in atherosclerosis of larger blood vessels. The present studies are designed to investigate this proposed synergistic interaction between altered glomerular hemodynamics, e.g., glomerular hypertension, and abnormal lipid metabolism in the pathogenesis of FGS. We plan to utilize well defined experimental manuevers in rats to alter circulating lipids and/or glomerular hemodynamics. Micropuncture and histologic evaluation of renal tissue will be performed to assess functional-structural correlations. Results of these studies may lead to a better understanding of the pathogenesis of glomerular injury, as well as to new approaches for patients with renal diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK037396-02
Application #
3236277
Study Section
General Medicine B Study Section (GMB)
Project Start
1986-07-01
Project End
1989-06-30
Budget Start
1987-07-01
Budget End
1988-06-30
Support Year
2
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Hennepin County Medical Center (Minneapolis)
Department
Type
DUNS #
City
Minneapolis
State
MN
Country
United States
Zip Code
55415
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Schmitz, P G; O'Donnell, M P; Kasiske, B L et al. (1991) Glomerular hemodynamic effects of dietary polyunsaturated fatty acid supplementation. J Lab Clin Med 118:129-35
O'Donnell, M P; Kasiske, B L; Schmitz, P G et al. (1990) High protein intake accelerates glomerulosclerosis independent of effects on glomerular hemodynamics. Kidney Int 37:1263-9
Opsahl, J A; Abraham, P A; Keane, W F (1990) Renal effects of angiotensin converting enzyme inhibitors: nondiabetic chronic renal disease. Cardiovasc Drugs Ther 4:221-8
Keane, W F; Kasiske, B L; O'Donnell, M P et al. (1989) Therapeutic implications of lipid-lowering agents in the progression of renal disease. Am J Med 87:21N-24N
Schmitz, P G; Kasiske, B L; O'Donnell, M P et al. (1989) Lipids and progressive renal injury. Semin Nephrol 9:354-69