Human low-density lipoprotein (LDL) is taken up by rat mesangial cells in a receptor-dependent manner, although lipoprotein metabolism and lipoprotein receptors differ substantially between rodents and humans. We therefore compared binding and uptake kinetics as well as intracellular cholesterol metabolism of apoB- and apoB,E-containing lipoproteins in rat and human mesangial cells. Uptake of very-low-density lipoprotein (VLDL) and LDL in both human and rat mesangial cells occurred in a receptor-specific, concentration-dependent manner and the process was saturable. However, LDL uptake specificity, receptor affinity and maximal degradation capacity was remarkably lower in rat than in human mesangial cells. Exposure of cells to LDL suppressed intracellular sterol synthesis more effectively in the human than in the rat cell line (87 vs. 36%, respectively). Additionally, cholesteryl ester formation was enhanced 23-fold by LDL in human as compared to rat mesangial cells. In contrast, degradation capacities of VLDL were higher in rat and uptake specificity as well as receptor affinity were similar. Inhibition of intracellular cholesterol synthesis and oleate formation rate by VLDL occurred to a similar extent in both cell lines. The data demonstrate that mesangial cell uptake of apoB-containing lipoproteins depends on the species investigated, whereas apoE-rich lipoprotein particles are taken up independent of species. Therefore, human mesangial cells should be preferred over rat mesangial cells when investigating lipoprotein metabolism to elucidate the potential role of lipoproteins in mediating glomerular injury and progression of renal disease in man.