Angiotensin-converting enzyme inhibitors (ACEi) provide renoprotection. A low sodium diet enhances their efficacy. However, the added effect of sodium restriction on proteinuria and blood pressure is not invariably associated with better preservation of renal morphology, suggesting that the combination of ACEi with a low sodium diet can elicit renal structural abnormalities. To test this hypothesis, the effects of ACEi in combination with a control (CS) or a low sodium (LS) diet were investigated in healthy rats and in adriamycin nephrotic rats. After 3 weeks of treatment, rats were sacrificed and kidneys examined for renal structural abnormalities. In healthy rats, ACEi reduced blood pressure: the fall in blood pressure was significantly greater in the ACEi/LS group. Renal morphology was normal in the ACEi/CS group but severe interstitial damage was found in the ACEi/LS group. This was associated with increased interstitial macrophage influx and up-regulation of osteopontin, alpha-smooth muscle actin, and collagen III expression. In addition, ACEi/LS induced an increase in the total medial area of afferent arterioles. In nephrotic rats, ACEi/LS reduced both blood pressure and proteinuria, whereas only blood pressure was reduced in the ACEi/CS group. Mild interstitial damage was present in the ACEi/CS group but, strikingly, pronounced tubulo-interstitial abnormalities occurred in the ACEi/LS group, similar to those seen in ACEi/LS healthy rats, with similar changes in afferent arteriolar walls. In conclusion, the combination of ACEi/LS elicits pronounced renal interstitial abnormalities in healthy and nephrotic rats, despite a significant reduction of proteinuria in the latter. Considering their occurrence in healthy rats, these renal adverse effects cannot be due to specific characteristics of adriamycin nephrosis. Further studies should elucidate the mechanisms underlying these observations and their impact on long-term renoprotection.