The effect of the ionic form of gadolinium, a trivalent lanthanide, on the endocytic uptake of albumin was investigated in HK-2 cells, a human renal proximal tubular epithelial cell line. When HK-2 cells were pretreated with gadolinium, the uptake of fluorescein isothiocyanate-labeled albumin (FITC-albumin) was enhanced in a time- and concentration-dependent manner. The uptake of FITC-albumin enhanced by gadolinium was partially but significantly decreased by unlabeled albumin, indicating that gadolinium increased, at least in part, a specific uptake system of albumin.  Pretreatment of the cells with gadolinium in the presence of diethylenetriaminepentaacetic acid (DTPA), a chelating agent, completely abolished the stimulating effect of gadolinium on FITC-albumin uptake. Furthermore, the enhanced uptake of FITC-albumin was significantly inhibited by caveolin-dependent endocytosis inhibitors (methyl-β-cyclodextrin and nystatin) and macropinocytosis inhibitors [cytochalasin D and 5-(N-ethyl-N-isopropyl)amiloride], but not by a clathrin-dependent endocytosis inhibitor chlorpromazine. Like FITC-albumin, the internalization of FITC-dextran and FITC-inulin, markers of fluid-phase endocytosis/macropinocytosis, was enhanced by gadolinium treatment in a concentration- dependent manner. These findings indicate that gadolinium might stimulate the endocytic uptake of albumin via caveolin-dependent endocytosis and macropinocytosis in HK-2 cells.