title: 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.
authors.affiliation: Department of Pediatrics, Kyorin University School of Medicine, Mitaka, Tokyo, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Ito
authors.forename: Yukino
authors.initials: Y
authors.lastname: Nishibori
authors.forename: Yugo
authors.initials: Y
authors.lastname: Ito
authors.forename: Hisashi
authors.initials: H
authors.lastname: Takagi
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Akimoto
authors.forename: Akihiko
authors.initials: A
authors.lastname: Kudo
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Asanuma
authors.forename: Yoshimichi
authors.initials: Y
authors.lastname: Sai
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Miyamoto
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Takenaka
authors.forename: Kunimasa
authors.initials: K
authors.lastname: Yan
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D000068338:Everolimus; D005455:Fluorescent Antibody Technique; D007150:Immunohistochemistry; D018613:Microscopy, Confocal; D009402:Nephrosis, Lipoid / Q000209:etiology / Q000378:metabolism*; D050199:Podocytes / Q000378:metabolism*; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020123:Sirolimus / Q000031:analogs & derivatives; D018709:Statistics, Nonparametric; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D056811:Unfolded Protein Response / Q000502:physiology*
chemical_list: D000068338:Everolimus; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus