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 - Publisher 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 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.
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 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.
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U2 - 10.1681/ASN.2016050519
DO - 10.1681/ASN.2016050519
M3 - Article
C2 - 28270414
AN - SCOPUS:85017435939
SN - 1046-6673
VL - 28
SP - 2144
EP - 2157
JO - Journal of the American Society of Nephrology
JF - Journal of the American Society of Nephrology
IS - 7
ER -