Research ExplorerPublicationsTargeting mTOR Signaling Can Prevent the Progression of FSGS

Targeting mTOR Signaling Can Prevent the Progression of FSGS

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Targeting mTOR Signaling Can Prevent the Progression of FSGS. / Zschiedrich, Stefan; Bork, Tillmann; Liang, Wei; Wanner, Nicola; Eulenbruch, Kristina; Munder, Stefan; Hartleben, Björn; Kretz, Oliver; Gerber, Simon; Simons, Matias; Viau, Amandine; Burtin, Martine; Wei, Changli; Reiser, Jochen; Herbach, Nadja; Rastaldi, Maria-Pia; Cohen, Clemens D; Tharaux, Pierre-Louis; Terzi, Fabiola; Walz, Gerd; Gödel, Markus; Huber, Tobias B.

In: J AM SOC NEPHROL, Vol. 28, No. 7, 07.2017, p. 2144-2157.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

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, CD, Tharaux, P-L, Terzi, F, Walz, G, Gödel, M & Huber, TB 2017, 'Targeting mTOR Signaling Can Prevent the Progression of FSGS', J AM SOC NEPHROL, vol. 28, no. 7, pp. 2144-2157. https://doi.org/10.1681/ASN.2016050519

APA

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. J AM SOC NEPHROL, 28(7), 2144-2157. https://doi.org/10.1681/ASN.2016050519

Vancouver

Zschiedrich S, Bork T, Liang W, Wanner N, Eulenbruch K, Munder S et al. Targeting mTOR Signaling Can Prevent the Progression of FSGS. J AM SOC NEPHROL. 2017 Jul;28(7):2144-2157. https://doi.org/10.1681/ASN.2016050519

Bibtex

@article{906fda178c4e4fe0aa3c41def8ba05f8,
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 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 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.",
keywords = "Animals, Disease Progression, Glomerulosclerosis, Focal Segmental, Humans, Immunosuppressive Agents, Mice, Multiprotein Complexes, Signal Transduction, Sirolimus, TOR Serine-Threonine Kinases, Journal Article",
author = "Stefan Zschiedrich and Tillmann Bork and Wei Liang and Nicola Wanner and Kristina Eulenbruch and Stefan Munder and Bj{\"o}rn Hartleben and Oliver Kretz and Simon Gerber and Matias Simons and Amandine Viau and Martine Burtin and Changli Wei and Jochen Reiser and Nadja Herbach and Maria-Pia Rastaldi and Cohen, {Clemens D} and Pierre-Louis Tharaux and Fabiola Terzi and Gerd Walz and Markus G{\"o}del and Huber, {Tobias B}",
note = "Copyright {\textcopyright} 2017 by the American Society of Nephrology.",
year = "2017",
month = jul,
doi = "10.1681/ASN.2016050519",
language = "English",
volume = "28",
pages = "2144--2157",
journal = "J AM SOC NEPHROL",
issn = "1046-6673",
publisher = "American Society of Nephrology",
number = "7",

}

RIS

TY - JOUR

T1 - Targeting mTOR Signaling Can Prevent the Progression of FSGS

AU - Zschiedrich, Stefan

AU - Bork, Tillmann

AU - Liang, Wei

AU - Wanner, Nicola

AU - Eulenbruch, Kristina

AU - Munder, Stefan

AU - Hartleben, Björn

AU - Kretz, Oliver

AU - Gerber, Simon

AU - Simons, Matias

AU - Viau, Amandine

AU - Burtin, Martine

AU - Wei, Changli

AU - Reiser, Jochen

AU - Herbach, Nadja

AU - Rastaldi, Maria-Pia

AU - Cohen, Clemens D

AU - Tharaux, Pierre-Louis

AU - Terzi, Fabiola

AU - Walz, Gerd

AU - Gödel, Markus

AU - Huber, Tobias B

N1 - Copyright © 2017 by the American Society of Nephrology.

PY - 2017/7

Y1 - 2017/7

N2 - 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 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 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.

AB - 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 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 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.

KW - Animals

KW - Disease Progression

KW - Glomerulosclerosis, Focal Segmental

KW - Humans

KW - Immunosuppressive Agents

KW - Mice

KW - Multiprotein Complexes

KW - Signal Transduction

KW - Sirolimus

KW - TOR Serine-Threonine Kinases

KW - Journal Article

U2 - 10.1681/ASN.2016050519

DO - 10.1681/ASN.2016050519

M3 - SCORING: Journal article

C2 - 28270414

VL - 28

SP - 2144

EP - 2157

JO - J AM SOC NEPHROL

JF - J AM SOC NEPHROL

SN - 1046-6673

IS - 7

ER -