Targeting mTOR signaling can prevent the progression of FSGS

Stefan Zschiedrich, Tillmann Bork, Wei Liang, Nicola Wanner, Kristina Eulenbruch, Stefan Munder, Björn Hartleben, Oliver Kretz, Simon Gerber, Matias Simons, Amandine Viau, Martine Burtin, Changli Wei, Jochen Reiser, Nadja Herbach, Maria Pia Rastaldi, Clemens D. Cohen, Pierre Louis Tharaux, Fabiola Terzi, Gerd WalzMarkus Gödel, Tobias B. Huber

Research output: Contribution to journalArticle

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 patientswith FSGS and amurine FSGSmodel. Furthermore, amousemodel with constitutive mTORC1 activation closely recapitulated human FSGS. Notably, the complete knockout of mTORC1 by induced deletion of both Raptor alleles accelerated the progression of murine FSGS models. However, lowering mTORC1 signaling by deleting just one Raptor allele ameliorated the progression of glomerulosclerosis. Similarly, low-dose treatmentwith themTORC1 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. ProlongedmTOR activation, however, results in a metabolic podocyte reprogramming leading to increased cellular stress and dedifferentiation, thus offering a treatment rationale for incomplete mTOR inhibition.

Original languageEnglish
Pages (from-to)2144-2157
Number of pages14
JournalJournal of the American Society of Nephrology
Volume28
Issue number7
DOIs
Publication statusPublished - Jul 1 2017

ASJC Scopus subject areas

  • Nephrology

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    Zschiedrich, S., Bork, T., Liang, W., Wanner, N., Eulenbruch, K., Munder, S., Hartleben, B., Kretz, O., Gerber, S., Simons, M., Viau, A., Burtin, M., Wei, C., Reiser, J., Herbach, N., Rastaldi, M. P., Cohen, C. D., Tharaux, P. L., Terzi, F., ... Huber, T. B. (2017). Targeting mTOR signaling can prevent the progression of FSGS. Journal of the American Society of Nephrology, 28(7), 2144-2157. https://doi.org/10.1681/ASN.2016050519