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

Abstract

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.

Essential Role of X-Box Binding Protein-1 during Endoplasmic Reticulum Stress in Podocytes

“…4 Recent evidence has suggested a robust increase in podocyte BiP due to ER stress caused by Pierson syndrome (laminin mutations), Alport syndrome, thin membrane basement disease (collagen IV mutations), Heymann nephritis, puromcyin-induced nephrosis, and mesangioproliferative GN. [5][6][7][8] Therefore, in the current study, we first verified that treatment of cultured podocytes with tunicamycin, an agent that inhibits N-glycosylation of proteins in the ER, results in an increase in ER stress and activation of the UPR. This effect was further validated in vivo by glomeruli isolated from mice injected with rabbit-anti-mouse glomerular basement membrane nephrotoxic sera (NTS).…”

“…22 This fundamental machinery is also elicited in podocytes; previous reports have revealed increased expression of molecular chaperones and the UPR in vitro after albumin administration 23,24 and in vivo after experimental glomerular injury in rodents. 7,8,25 Furthermore, upregulation of ER stress proteins in human kidney biopsy specimens taken from patients harboring laminin and collagen IV mutations, 7,8 patients with underlying diabetic nephropathy, 26,27 and patients with FSGS 28,29 suggests the fundamental role of the UPR in podocyte biology. The GRP78 activation observed in a variety of glomerular diseases is likely an adaptive cellular process, which meets the demands of a pathologic condition and may arise irrespective of disease progression.…”

Ursodeoxycholic acid and 4-phenylbutyrate prevent endoplasmic reticulum stress-induced podocyte apoptosis in diabetic nephropathy

“…6 ER stress occurs when homeostasis is disturbed. It can be induced by hyperglycemia, reactive oxygen species (ROS), free fatty acids and other mediators in the presence of diabetes, 7 with the accumulation of unfolded proteins in ER.…”

Transforming Growth Factor β1-induced Apoptosis in Podocytes via the Extracellular Signal-regulated Kinase-Mammalian Target of Rapamycin Complex 1-NADPH Oxidase 4 Axis

“…Increased mTOR activity has been reported in different glomerular diseases, and mTORC1 inhibition by rapamycin and everolimus shows beneficial effects against diabetic nephropathy, focal segmental glomerulosclerosis, minimal change disease, membranous nephropathy, etc. (7)(8)(9)(10). But contrasting evidence also indicates that mTORC1 inhibition by the immunosuppressive drug rapamycin leads proteinuria and podocyte apoptosis and develops primary focal segmental glomerulosclerosis in renal transplant recipients (11).…”