Conversion to rapamycin from calcineurin inhibitors may contribute to improvement of graft function in kidney transplant recipients, especially in patients with calcineurin inhibitor-related nephrotoxicity. The conversion from calcineurin inhibitors to rapamycin in kidney transplant recipients has been associated with a higher incidence of proteinuria. It could be explained by possible hemodynamic changes due to withdrawal of calcineurin inhibitors. Podocyte damage occurs commonly in rapamycin-related proteinuria. The vascular endothelial growth factor system has been suggested to be implicated in mammalian target of rapamycin inhibitor-associated proteinuria. However, induction of urokinase receptor (uPAR) signaling in podocytes leads to foot process effacement and urinary protein. In this study, we assessed the role of uPAR in primary cultured podocytes with rapamycin treatment. Our results indicate that 24-hour rapamycin treatment promotes podocyte migration on the wound scratch assay in a dose-dependent manner. Rapamycin treatment for 2 days does not increase the apoptosis of podocytes or affect the podocyte cell viability and morphology. The up-regulation of uPAR in podocytes was confirmed by immunofluorescence staining, real-time polymerase chain reaction (1.8 ± 0.3-fold increase of relative quantification; P < .01) and Western blot analysis. Rapamycin treatment also causes the activation of FAK and ILK in a dose-dependent manner. In summary, rapamycin could promote podocyte migration through the up-regulation of uPAR. This finding provides a new mechanism of rapamycin-associated proteinuria. It also suggests that pharmacologic inhibition of uPAR signaling cascade may have therapeutic potential in the setting of rapamycin-related proteinuria.
