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.
