The aim of this study is to investigate the role of the proximal tubule in microalbuminuria in the early stage of diabetic nephropathy. Diabetes was induced in male Sprague-Dawley rats by an injection of streptozotocin (50 mg/kg, i.v.). After 2 weeks, albumin delivery in the proximal tubule was measured using micropuncture and the endocytosis process of FITC-labeled albumin was evaluated with immunoelectron microscopy. Albumin was significantly reabsorbed in the proximal convoluted tubule (PCT) of controls (0.39+/-0.05 ng/min at early PCT to 0.17+/-0.08 at late PCT, P<0.05), whereas albumin reabsorption was inhibited in diabetic rats (0.27+/-0.05 to 0.21+/-0.08). Immunogold study revealed that FITC-albumin was significantly less reabsorbed in endosomes and lysosomes of S1 segments in diabetic rats than in controls (endosome: 1.20+/-0.10 vs 2.16+/-0.15 microm-1, P<0.0001; lysosome: 0.26+/-0.03 vs 0.83+/-0.07, P<0.0001). The expression of megalin, an endocytosis receptor, was decreased at the apical membrane of PCT in diabetic rats. The lipid peroxidation production in the proximal tubule was significantly increased in diabetic rats. In conclusion, albuminuria in early-stage diabetic rats can be partly explained by a decreased albumin endocytosis with reduced megalin expression and with increased lipid peroxidation in the proximal tubule.