Enalapril and low protein reverse chronic puromycin aminonucleoside nephropathy. The effects of dietary protein and converting enzyme inhibition (CEI) on chronic puromycin aminonucleoside nephropathy (PAN) were studied. PAN was induced with seven SQ injections of puromycin aminonucleoside 20 mg/kg over 10 weeks in male Sprague-Dawley rats. The rats were divided into a 22.5% protein diet group (Gr 1), a 6% protein diet group (Gr 2), and an enalapril-treated group on 22.5% protein diet (Gr 3). Group 4 animals served as age-matched controls. Both diets were isocaloric and had the same phosphorus content. Rats from groups 1, 2, and 4 were sacrificed at 12, 18 and 24 weeks. Five rats of group 3 were sacrificed at 12 weeks, and the others were divided in subgroups 3A (diet changed to 6% protein) and 3B (no changes); half of each subgroup was sacrificed at 18 and 24 weeks, respectively. Group 2 had significantly less proteinuria than group 1 at all times. Group 3 had the same proteinuria as group 1 until 12 weeks and then began to decrease. In group 3A proteinuria decreased to group 2 levels, while in group 3B the decrease was slower but still prominent. Early lesions of focal and segmental glomerular sclerosis/hyalinosis (FSH) were present in groups 1, 2, 3 at 12 weeks (16 ± 1.2%, 15 ± 1.3%, 7 ± 1.3%, respectively, versus 1.3 ± 0.4% in controls), but by 18 weeks a reversal in FSH was seen in groups 2 and 3A/B (3 ± 1.6%, 2 ± 0.4%, and 3 ± 0.9%, respectively, vs. 14 ± 1.5% in group 1). This reversal persisted at 24 weeks (5 ± 2.5%, 3 ± 0.8%, 4 ± 0.8% vs. 18 ± 2.6%). At 24 weeks mean glomerular diameter was significantly less in group 2 compared to group 1, 100.7 ± 2.0 µ versus 112.2 ± 2.7 µ, P = 0.009. In summary, both low protein diet and CEI for 24 weeks reversed both proteinuria and early FSH lesions in chronic PAN after cessation of PA injections.