EFFECTS OF DIETARY-PROTEIN, ANGIOTENSIN-I CONVERTING-ENZYME INHIBITION AND MESANGIAL OVERLOAD ON THE PROGRESSION OF ADRIAMYCIN-INDUCED NEPHROPATHY

Adriamycin, a commonly used antineoplastic antibiotic, induces glomeru lar lesions in rats, resulting in persistent proteinuria and glomerulo sclerosis. We studied the effects of dietary protein and of an angiote nsin I converting enzyme inhibitor on the progression of this nephropa thy and the evolution of the histological lesions, as well as mesangia l macromolecule flow. Adriamycin nephropathy was induced by injecting a single iv dose of adriamycin (3 mg/kg body weight) into the tail vei n of male Wistar rats (weight, 180-200 g). In Experiment I animals wit h adriamycin-induced nephropathy were fed diets containing 6% (Low-Pro tein Diet Group = LPDG), 20% (Normal-Protein Diet Group = NPDG) and 40 % (High-protein Diet Group = HPDG) protein and were observed for 30 we eks. In Experiment II the rats with adriamycin nephropathy were divide d into 2 groups: ADR, that received adriamycin alone, and ADR-ENA, tha t received adriamycin plus enalapril, an angiotensin I converting enzy me inhibitor. The animals were sacrificed after a 24-week observation period. Six hours before sacrifice the animals were injected with I-13 1-ferritin and the amount of I-131-ferritin in the glomeruli was measu red. In Experiment III, renal histology was performed 4, 8 and 16 week s after adriamycin injection. At the end of Experiment I the tubuloint erstitial 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, 4 2.6 +/- 6% in NPDG, and 54 +/- 9% in HPDG (P<0.05); and proteinuria wa s 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 AD R-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 I-131-f erritin in the mesangium was 214.26 +/- 22.71 cpm/mg protein in ADR an d 253.77 +/- 69.72 cpm/mg protein in ADR-ENA (P>0.05). In Experiment I II, sequential histological analysis revealed an acute tubulointerstit ial cellular infiltrate at week 4, which was decreased at week 8. Tubu lar casts and dilatation were first seen at week 8 and increased at we ek 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.