mTORC1 activation triggers the unfolded protein response in podocytes and leads to nephrotic syndrome

Although podocyte damage is known to be responsible for the development of minimal-change disease (MCD), the underlying mechanism remains to be elucidated. Previously, using a rat MCD model, we showed that endoplasmic reticulum (ER) stress in the podocytes was associated with the heavy proteinuric state and another group reported that a mammalian target of rapamycin complex 1 (mTORC1) inhibitor protected against proteinuria. In this study, which utilized a rat MCD model, a combination of immunohistochemistry, dual immunofluorescence and confocal microscopy, western blot analysis, and quantitative real-time RT-PCR revealed co-activation of the unfolded protein response (UPR), which was induced by ER stress, and mTORC1 in glomerular podocytes before the onset of proteinuria and downregulation of nephrin at the post-translational level at the onset of proteinuria. Podocyte culture experiments revealed that mTORC1 activation preceded the UPR that was associated with a marked decrease in the energy charge. The mTORC1 inhibitor everolimus completely inhibited proteinuria through a reduction in both mTORC1 and UPR activity and preserved nephrin expression in the glomerular podocytes. In conclusion, mTORC1 activation may perturb the regulatory system of energy metabolism primarily by promoting energy consumption and inducing the UPR, which underlie proteinuria in MCD. Laboratory Investigation (2011) 91, 1584-1595; doi: 10.1038/labinvest. 2011.135; published online 29 August 2011