title: Targeting mTOR Signaling Can Prevent the Progression of FSGS.
abstract: Mammalian target of rapamycin (mTOR) signaling is involved in a variety of kidney diseases. Clinical trials administering mTOR inhibitors to patients with FSGS, a prototypic podocyte disease, led to conflicting results, ranging from remission to deterioration of kidney function. Here, we combined complex genetic titration of mTOR complex 1 (mTORC1) levels in murine glomerular disease models, pharmacologic studies, and human studies to precisely delineate the role of mTOR in FSGS. mTORC1 target genes were significantly induced in microdissected glomeruli from both patients with FSGS and a murine FSGS model. Furthermore, a mouse model with constitutive mTORC1 activation closely recapitulated human FSGS. Notably, the complete knockout of mTORC1 by induced deletion of bothRaptoralleles accelerated the progression of murine FSGS models. However, lowering mTORC1 signaling by deleting just oneRaptorallele ameliorated the progression of glomerulosclerosis. Similarly, low-dose treatment with the mTORC1 inhibitor rapamycin efficiently diminished disease progression. Mechanistically, complete pharmacologic inhibition of mTOR in immortalized podocytes shifted the cellular energy metabolism toward reduced rates of oxidative phosphorylation and anaerobic glycolysis, which correlated with increased production of reactive oxygen species. Together, these data suggest that podocyte injury and loss is commonly followed by adaptive mTOR activation. Prolonged mTOR activation, however, results in a metabolic podocyte reprogramming leading to increased cellular stress and dedifferentiation, thus offering a treatment rationale for incomplete mTOR inhibition.
authors.affiliation: Department of Medicine IV, Faculty of Medicine, University of Freiburg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Zschiedrich
authors.affiliation: Department of Medicine IV, Faculty of Medicine, University of Freiburg, Germany.
authors.forename: Tillmann
authors.initials: T
authors.lastname: Bork
authors.affiliation: Department of Medicine IV, Faculty of Medicine, University of Freiburg, Germany.|Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Liang
authors.affiliation: Department of Medicine IV, Faculty of Medicine, University of Freiburg, Germany.
authors.forename: Nicola
authors.initials: N
authors.lastname: Wanner
authors.affiliation: Department of Medicine IV, Faculty of Medicine, University of Freiburg, Germany.
authors.forename: Kristina
authors.initials: K
authors.lastname: Eulenbruch
authors.affiliation: Department of Medicine IV, Faculty of Medicine, University of Freiburg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Munder
authors.affiliation: Department of Medicine IV, Faculty of Medicine, University of Freiburg, Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: Hartleben
authors.affiliation: Department of Medicine IV, Faculty of Medicine, University of Freiburg, Germany.|BIOSS Centre for Biological Signalling Studies, and.
authors.forename: Oliver
authors.initials: O
authors.lastname: Kretz
authors.affiliation: Imagine Institute, Institut national de la santé et de la recherche médicale (INSERM) U1163, Paris Descartes University-Sorbonne Paris Cité, Paris, France.
authors.forename: Simon
authors.initials: S
authors.lastname: Gerber
authors.affiliation: Imagine Institute, Institut national de la santé et de la recherche médicale (INSERM) U1163, Paris Descartes University-Sorbonne Paris Cité, Paris, France.
authors.forename: Matias
authors.initials: M
authors.lastname: Simons
authors.affiliation: Department of Medicine IV, Faculty of Medicine, University of Freiburg, Germany.
authors.forename: Amandine
authors.initials: A
authors.lastname: Viau
authors.affiliation: Institut national de la santé et de la recherche médicale (INSERM) U1151, Université Paris Descartes, Institut Necker Enfants Malades, Hopital Necker, Paris, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Burtin
authors.affiliation: Department of Medicine, Rush University Medical Center, Chicago, IL.
authors.forename: Changli
authors.initials: C
authors.lastname: Wei
authors.affiliation: Department of Medicine, Rush University Medical Center, Chicago, IL.
authors.forename: Jochen
authors.initials: J
authors.lastname: Reiser
authors.affiliation: Institute of Veterinary Pathology, Centre for Clinical Veterinary Medicine, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Nadja
authors.initials: N
authors.lastname: Herbach
authors.affiliation: Renal Research Laboratory, Fondazione Istituto di ricovero e cura a carattere scientifico (IRCCS) Ospedale Maggiore Policlinico and Fondazione D'Amico, Milan, Italy.
authors.forename: Maria-Pia
authors.initials: MP
authors.lastname: Rastaldi
authors.affiliation: Division of Nephrology, Hypertension and Clinical Immunology, Städtisches Klinikum München, Munich, Germany.
authors.forename: Clemens D
authors.initials: CD
authors.lastname: Cohen
authors.affiliation: Paris Cardiovascular Research Centre (PARCC), Institut National de la Santé et de la Recherche Médicale, Paris, France; and.
authors.forename: Pierre-Louis
authors.initials: PL
authors.lastname: Tharaux
authors.affiliation: Institut national de la santé et de la recherche médicale (INSERM) U1151, Université Paris Descartes, Institut Necker Enfants Malades, Hopital Necker, Paris, France.
authors.forename: Fabiola
authors.initials: F
authors.lastname: Terzi
authors.affiliation: Department of Medicine IV, Faculty of Medicine, University of Freiburg, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Walz
authors.affiliation: Department of Medicine IV, Faculty of Medicine, University of Freiburg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Gödel
authors.affiliation: Department of Medicine IV, Faculty of Medicine, University of Freiburg, Germany; tobias.huber@uniklinik-freiburg.de.|BIOSS Centre for Biological Signalling Studies, and.|Center for Systems Biology (ZBSA), Albert-Ludwigs-University Freiburg, Freiburg, Germany.|Department of Medicine III, Faculty of Medicine University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Tobias B
authors.initials: TB
authors.lastname: Huber
mesh_terms: D000818:Animals; D018450:Disease Progression; D005923:Glomerulosclerosis, Focal Segmental / Q000209:etiology* / Q000517:prevention & control*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors* / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000494:pharmacology* / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology*
chemical_list: D007166:Immunosuppressive Agents; D046912:Multiprotein Complexes; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: Pathophysiology of Renal Disease and Progression; focal segmental glomerulosclerosis; mTOR; mitochondrial function; rapamycin; raptor