Modulation of incipient glomerular lesions in experimental diabetic nephropathy by hypotensive and subhypotensive dosages of an ACE inhibitor

A glomerular permeability defect occurs early in the course of type 1 diabe tes and precedes the onset of microalbuminuria and renal morphological chan ges. Recently, ACE inhibitors have been shown to prevent loss of glomerular membrane permselective function, but the mechanism of this nephroprotectiv e effect is still being debated. The objective of the present study was to evaluate the effects of hypotensive and subhypotensive dosages of the ACE i nhibitor quinapril ex vivo and of its active metabolite quinaprilat in vitr o on the glomerular albumin permeability (P-alb) defect in the early phases of experimental diabetes. For the ex vivo study, six groups of male Wistar rats were evaluated for 4 weeks. One group served as a nondiabetic control (C); the other five groups were rendered diabetic and included untreated d iabetic rats (D) and diabetic rats receiving quinapril at the dosages of 5 (DQ1), 2.5 (DQ2), 1.25 (DQ3), and 0.625 (DQ4) mg . kg(-1) . day(-1). Dosage -dependent effects of quinapril on systolic blood pressure and the glomerul ar filtration rate were observed. In contrast, control of P-alb, in isolate d glomeruli exposed to oncotic gradients, proteinuria, and glomerular and t ubular hypertrophy was obtained with subhypotensive dosages (DQ3 and DQ4 gr oups) of the ACE inhibitor. In the in vitro study, quinaprilat reduced P-al b significantly in concentration ranges from 10(-6) to 10(-14) mol/l compar ed with results in control glomeruli. The effect on P-alb may have occurred by mechanisms different from kidney ACE inhibitor. These study results ind icated that ACE inhibitor treatment prevents the early onset of the P-alb d efect in experimental diabetes. This effect seemed to occur independently o f systemic or glomerular hemodynamic changes and, at least partially, from kidney ACE inhibition.