Inhibitors of HMG-CoA reductase reduce receptor-mediated endocytosis in human kidney proximal tubular cells

Abstract

The proximal tubular cells of the kidney are responsible for reabsorption of proteins from the tubular lumen. In a study using Opossum kidney (OK) cells, receptor-mediated protein endocytosis was reduced by statins, inhibitors of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase, which are widely used for therapeutic reduction of plasma cholesterol levels. To explore the possible clinical relevance of the observations in OK cells, protein endocytosis in human kidney tubular cells was investigated in the presence and absence of statins. The uptake of FITC-labeled albumin in these cultures of human kidney tubular cells was investigated by microscopy, flow cytometry and spectrofluorometry. Protein uptake occurred selectively into proximal tubular cells while it was absent in distal tubular/collecting duct cells. Three statins (simvastatin, pravastatin, and rosuvastatin) significantly inhibited the uptake of protein in a concentration-dependent way. This inhibitory effect of statins could be prevented by the co-addition of mevalonate, the product of HMG-CoA reductase. This effect was not the result of a statin-induced cytotoxicity since cell-viability was unaffected. Finally, it was demonstrated that statins strongly inhibited cholesterol synthesis in the human kidney tubular cells. These data suggest that statins have the potential to inhibit albumin uptake by the human proximal nephron as a result of inhibition of HMG-CoA reductase in the proximal tubule cells. Taken into account the data of the accompanying manuscript this inhibitory effect most probably results from a reduced prenylation of some proteins critically involved in endocytosis. It is suggested that these data help to explain the occurrence of proteinuria in some patients treated with high statin doses.