Because most renal diseases progress, almost all kidney patients can expect to eventually require dialysis or transplantation. Studies in animals suggest that progression results from increased pressure within glomerular capillaries of damaged kidneys. However, questions concerning the relevance of these observations to nonhypertensive renal diseases and the effectiveness of new antihypertensive agents and dietary therapies in preventing progressive renal disease remain unanswered. In this study, clearance, micropuncture and morphologic techniques will be used to examine these issues in 3 nonimmunologic models of renal disease. Protocol 1 will develop the rat recovering from desoxycorticosterone-salt (DOC-SALT) hypertension as a new model of focal glomerular sclerosis, correlating morphologic studies of glomerular structure with micropuncture measurements of glomerular hemodynamics in these rats. Since protein restriction and converting enzyme inhibition prevent hemodynamically mediated glomerular injury in hypertensive animals, their effects on this model will be examined. These studies will provide the first analysis of the role of hemodynamic factors in a nondiabetic, normotensive glomecrular disease, and determine whether glomerular injury can be ameliorated by drug or dietary therapy in the absence of systemic hypertension. Protocol 2 will examine the effects of calcium channel blockers and calcium supplementation on glomerular hemodynamics and injury in rats with DOC-SALT hypertension. Although increased dietary calcium has been proposed as a therapy for hypertension, preliminary studies suggest that such treatment may damage the kidney via a hemodynamic mechanism. This study will determine whether the adverse effect of calcium depends on entry of the cation into cells and/or is mediated by secondary increases in the production of vasodilator prostaglandins, and provide the first investigation of the effects of calcium blockers on hemodynamically-mediated glomerular injury. Protocol 3 will examine the effects of sodium restriction on glomerular function and injury in SHR. Once a mainstay of antihypertensive therapy, this dietary manipulation has largely been supplanted by the availability of potent diuertics and other hypotensive agents. Important recent data suggest that, independent of its effect on blood pressure, sodium restriction may retard the progression of hemodynamically mediated renal disease. Confirmation of this hypothesis might lead to increased utilization of this dietary therapy in the treatment of hypertension and renal insufficiency.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK038157-01A1
Application #
3237402
Study Section
General Medicine B Study Section (GMB)
Project Start
1987-09-20
Project End
1990-08-31
Budget Start
1987-09-20
Budget End
1988-08-31
Support Year
1
Fiscal Year
1987
Total Cost
Indirect Cost
Name
New York University
Department
Type
Schools of Medicine
DUNS #
004514360
City
New York
State
NY
Country
United States
Zip Code
10012
Lax, D S; Benstein, J A; Tolbert, E et al. (1992) Effects of salt restriction on renal growth and glomerular injury in rats with remnant kidneys. Kidney Int 41:1527-34
Dworkin, L D (1991) Effects of calcium antagonists on glomerular hemodynamics and structure in experimental hypertension. Am J Kidney Dis 17:89-93
Dworkin, L D; Feiner, H D; Parker, M et al. (1991) Effects of nifedipine and enalapril on glomerular structure and function in uninephrectomized SHR. Kidney Int 39:1112-7
Dworkin, L D (1990) Impact of calcium entry blockers on glomerular injury in experimental hypertension. Cardiovasc Drugs Ther 4:1325-30
Benstein, J A; Feiner, H D; Parker, M et al. (1990) Superiority of salt restriction over diuretics in reducing renal hypertrophy and injury in uninephrectomized SHR. Am J Physiol 258:F1675-81
Dworkin, L D (1990) Effects of calcium channel blockers on experimental glomerular injury. J Am Soc Nephrol 1:S21-7
Dworkin, L D; Levin, R I; Benstein, J A et al. (1990) Effects of nifedipine and enalapril on glomerular injury in rats with deoxycorticosterone-salt hypertension. Am J Physiol 259:F598-604
Dworkin, L D; Feiner, H D; Parker, M et al. (1990) Calcium carbonate exacerbates glomerular capillary hypertension and injury in rats with desoxycorticosterone-salt hypertension. Am J Hypertens 3:444-50
Dworkin, L D; Grosser, M; Feiner, H D et al. (1989) Renal vascular effects of antihypertensive therapy in uninephrectomized SHR. Kidney Int 35:790-8
Dworkin, L D; Benstein, J A (1989) Impact of antihypertensive therapy on progressive kidney damage. Am J Hypertens 2:162S-172S