To determined the effect of hypercholesterolemia induced by high-lipid diet on glomerulosclerosis.Urinary protein excretion and serum cholesterol were assayed, Image analysis and techniques of pathology, immunohistochemistry, molecular biology were used to determine morphological changes in glomeruli and the production of glomerular mesangial matrixes in adriamycin-induced nephrotic syndrome (NS) and non-NS rats fed with standard chow and high-lipid chow.The serum total cholesterol level was significantly higher in rats with high-lipid chow in both non-NS[(2.2 +/- 0.3) g/L vs (0.9 +/- 0.1) g/L, P < 0.01] and NS[(9.5 +/- 0.2) g/L vs (2.3 +/- 0.3) g/L, P < 0.01]. The urinary protein excretion was significantly higher in the high-lipid diet rats than that in standard chow rats [(76.2 +/- 24.2) mg/24 h vs (44.8 +/- 13.6) mg/24 h, P < 0.05] in NS rats. Significant increases in the mesangial matrix and mesangial cells were observed in rats with high-lipid diet in both NS and non-NS group. Especially, more obvious pathological changes were found in NS group, such as lipid deposits and foam cell formation in mesangial areas, and progressing to focal and segmental glomerulosclerosis in some glomeruli. The immunohistochemical assay showed that the production of fibronectin was increased in the rats with high-lipid diet in non-NS group, whereas, the production of three major components (collagen IV, fibronectin, and laminin) was increased in NS group, especially in the rats with high-lipid chow. The increased expression of laminin mRNA was also detected with slot blotting in both NS and non-NS rats with high-lipid chow, and it was more obvious in the rats with NS.Our findings indicated that diet-induced hyperlipidemia can lead to over-production of mesangial matrix components, and further aggravate glomerulosclerosis in adriamycin-induced nephrosis.