Modulation of Incipient Glomerular Lesions in Experimental Diabetic Nephropathy by Hypotensive and Subhypotensive Dosages of an ACE Inhibitor

Abstract

A glomerular permeability defect occurs early in the course of type 1 diabetes and precedes the onset of microalbuminuria and renal morphological changes. Recently, ACE inhibitors have been shown to prevent loss of glomerular membrane permselective function, but the mechanism of this nephroprotective effect is still being debated. The objective of the present study was to evaluate the effects of hypotensive and subhypotensive dosages of the ACE inhibitor quinapril ex vivo and of its active metabolite quinaprilat in vitro 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 diabetic rats (D) and diabetic rats receiving quinapril at the dosages of 5 (DQ1), 2.5 (DQ2), 1.25 (DQ3), and 0.625 (DQ4) mg ⅐ kg ؊1 ⅐ day ؊1 . Dosage-dependent effects of quinapril on systolic blood pressure and the glomerular filtration rate were observed. In contrast, control of P alb in isolated glomeruli exposed to oncotic gradients, proteinuria, and glomerular and tubular hypertrophy was obtained with subhypotensive dosages (DQ3 and DQ4 groups) of the ACE inhibitor. In the in vitro study, quinaprilat reduced P alb significantly in concentration ranges from 10 ؊6 to 10 ؊14 mol/l compared with results in control glomeruli. The effect on P alb may have occurred by mechanisms different from kidney ACE inhibitor. These study results indicated that ACE inhibitor treatment prevents the early onset of the P alb defect in experimental diabetes. This effect seemed to occur independently of systemic or glomerular hemodynamic changes and, at least partially, from kidney ACE inhibition. Diabetes 50

Endothelin A Receptor Blockade Reduces Diabetic Renal Injury via an Anti-Inflammatory Mechanism

“…ABT-627 treatment of sham rats also decreased ED-1-positive cells in the renal cortex; however, it is not clear whether the mechanism is similar in sham and hyperglycemic rats. Although renal hypertrophy was evident in HG rats, we did not observe significant structural changes in the kidney during this study, although some previous reports have shown glomerular enlargement, matrix expansion, interstitial fibrosis, and arteriolopathy during early diabetes in the STZ model (33)(34)(35)(36). These differences may be due to the strain or gender of rats used or the use of insulin to maintain moderate hyperglycemia.…”

Chronic endothelin-1 infusion elevates glomerular sieving coefficient and proximal tubular albumin reuptake in the rat

“…Recent studies have renewed interest in the role of proximal tubular uptake of albumin in protecting against albuminuria (Russo et al, 2007). In addition, changes in P alb on the order of magnitude that we observed in the chronic ET-1 model, 0.4 (Saleh et al, 2010a), are much less than those observed in rats displaying overt proteinuria associated with hyperglycemia, >0.8 (Fabris et al, 2001; Saleh et al, 2010b; Saleh et al, 2011). Several studies have established that an increase in glomerular permeability typically occurs prior to the development of overt proteinuria (Melnick et al, 1981; Bjorn et al, 1995; Sharma et al, 2002; Doublier et al, 2003).…”

Renal Processing of Albumin in Diabetes and Hypertension in Rats

“…There are, however, major differences with classic nephrosis in terms of (1) while there is a significant decrease in plasma albumin for diabetic and diabetic-hypertensive rats it does not compare to the >60% decrease observed in PAN and anti GBM GN [10]; (2) that the excreted protein is in the form of protein fragments as compared to the intact protein found in nephritis, and (3) the Fc of albumin is still considerably lower than the Fc of albumin measured for anti GBM GN and PAN. High levels of glomerular albumin permeability have been reported in studies of swollen isolated glomeruli obtained from STZ diabetic rats [43, 44]. While these results clearly reflect structural alterations in these glomeruli, it remains to be determined what quantitative relationship these in vitro permeability measurements have in relation to in vivo states.…”