Effects of dietary protein, angiotensin I converting enzyme inhibition and mesangial overload on the progression of adriamycin-induced nephropathy
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Adriamycin, a commonly used antineoplastic antibiotic, induces glomerular lesions in rats, resulting in persistent proteinuria and glomerulosclerosis. We studied the effects of dietary protein and of an angiotensin I converting enzyme inhibitor on the progression of this nephropathy and the evolution of the histological lesions, as well as mesangial macromolecule flow. Adriamycin nephropathy was induced by injecting a single iv dose of adriamycin (3 mg/kg body weight) into the tail vein of male Wistar rats (weight, 180-200 g). In Experiment I animals with adriamycin-induced nephropathy were fed diets containing 6% (Low-Protein Diet Group = LPDG), 20% (Normal-Protein Diet Group = NPDG) and 40% (High-Protein Diet Group = HPDG) protein and were observed for 30 weeks. In Experiment II the rats with adriamycin nephropathy were divided into 2 groups: ADR, that received adriamycin alone, and ADR-ENA, that received adriamycin plus enalapril, an angiotensin I converting enzyme inhibitor. The animals were sacrificed after a 24-week observation period. Six hours before sacrifice the animals were injected with 131I-ferritin and the amount of 131I-ferritin in the glomeruli was measured. In Experiment III, renal histology was performed 4, 8 and 16 weeks after adriamycin injection. At the end of Experiment I the tubulointerstitial lesion index was 2 for LPDG, 8 for NPDG, and 7.5 for HPDG (P < 0.05); the frequency of glomerulosclerosis was 19 ± 6.1% in LPDG, 42.6 ± 6% in NPDG, and 54 ± 9% in HPDG (P < 0.05); and proteinuria was 61.1 ± 25 mg/24 h in LPDG, 218.7 ± 27.5 mg/24 h in NPDG, and 324.5 ± 64.8 mg/24 h in HPDG (P < 0.05). In Experiment II, at sacrifice, 24-h proteinuria was 189 ± 16.1 mg in ADR, and 216 ± 26.1 mg in ADR-ENA (P > 0.05); the tubulointerstitial lesion index was 5 for ADR, and 5 for ADR-ENA (P > 0.05); the frequency of glomerulosclerosis was 40 ± 5.2% in ADR and 44 ± 6% in ADR-ENA (P > 0.05); the amount of 131I-ferritin in the mesangium was 214.26 ± 22.71 cpm/mg protein in ADR and 253.77 ± 69.72 cpm/mg protein in ADR-ENA (P > 0.05). In Experiment III, sequential histological analysis revealed an acute tubulointerstitial cellular infiltrate at week 4, which was decreased at week 8. Tubular casts and dilatation were first seen at week 8 and increased at week 16 when few glomerular lesions were found. The results suggest that the tubulointerstitial lesions may play a role in the development of glomerulosclerosis in adriamycin-induced nephropathy.