The Role of Angiotensin-II in Progressive Diabetic Glomerulopathy in the Rat*

Abstract

The potential pathogenic role of angiotensin-II (AII) in early progressive diabetic and renal ablation-induced glomerulosclerosis was explored and compared in the Sprague-Dawley (SD) rat and the mongrel dog. Male SD rats were divided into control and streptozotocin-treated (65 mg/kg, iv) groups. Unilateral surgical nephrectomy (Nx) was performed in half of each group. Enalapril (E; 50 mg/liter in the drinking water) was administered to half of each subgroup. Enalapril (high E; 250 mg/liter) was given to another 13 streptozotocin rats. All diabetic rats were treated with sc NPH insulin (4 U/day), and blood glucose was 520 +/- 124 mg/dl (mean +/- SD). Microalbuminuria was measured by RIA in 24-h urine collections; wet kidney weights were compared. [125I]AII binding assays were performed on isolated glomeruli. In control rats the high affinity binding dissociation constant (Kd) was 0.59 +/- 0.15 nM (n = 26; mean +/- SD) and receptor number (Ro) was 732 +/- 195 fmol/mg glomerular protein. At 3 weeks, the diabetic glomerular AII receptor Kd was 0.38 +/- 0.07 nM (n = 6; P less than 0.02 vs. control) and Ro was 784 +/- 97 fmol/mg protein (P = NS vs. control); diabetic high E Kd was 0.39 +/- 0.06 nM (n = 6; P less than 0.02 vs. control), and Ro was 873 +/- 105 fmol/mg protein (P = NS vs. diabetes without E). By 10 weeks, a Kd of 0.49 +/- 0.12 nM (n = 32; P less than 0.01 vs. control) and a Ro of 780 +/- 174 fmol/mg protein (P = NS vs. control) were observed when all of the diabetic group data were pooled. Neither Nx nor low or high dose E altered Ro. This is evidence that intraglomerular AII levels are normal or reduced after diabetes, Nx, or both. In the diabetic group, low dose E partially prevented, and high E abolished, Nx-enhanced microalbuminuria and renal hypertrophy. In nine pancreatectomized insulin-treated mongrel dogs over a 12- to 24-month period, despite moderately poor glucose control (300 +/- 75 mg/dl) and combined unilateral Nx in five dogs (12 months), elevated microalbuminuria was not observed. [125I]AII binding to isolated normal and diabetic dog glomeruli revealed the Kd to be of low affinity (1.86 +/- 0.28 to 13.80 +/- 1.88 nM), identifying the presence of type B receptors. Hence, the SD rat and mongrel dog differ in susceptibility to glomerular AII receptor type and progressive diabetic glomerulopathy.(ABSTRACT TRUNCATED AT 400 WORDS)