Targeting mTOR Signaling Can Prevent the Progression of FSGS Article Swipe
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 Walz
,
Markus Gödel
,
Tobias B. Huber
·
YOU?
·
· 2017
· Open Access
·
· DOI: https://doi.org/10.1681/asn.2016050519
YOU?
·
· 2017
· Open Access
·
· DOI: https://doi.org/10.1681/asn.2016050519
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.
Related Topics
Concepts
mTORC1
PI3K/AKT/mTOR pathway
Podocyte
Cancer research
Biology
Glomerulosclerosis
Cell biology
Endocrinology
Kidney
Signal transduction
Proteinuria
Metadata
- Type
- article
- Language
- en
- Landing Page
- https://doi.org/10.1681/asn.2016050519
- https://jasn.asnjournals.org/content/jnephrol/28/7/2144.full.pdf
- OA Status
- bronze
- Cited By
- 71
- References
- 59
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W2594291574
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
-
https://openalex.org/W2594291574Canonical identifier for this work in OpenAlex
- DOI
-
https://doi.org/10.1681/asn.2016050519Digital Object Identifier
- Title
-
Targeting mTOR Signaling Can Prevent the Progression of FSGSWork title
- Type
-
articleOpenAlex work type
- Language
-
enPrimary language
- Publication year
-
2017Year of publication
- Publication date
-
2017-03-07Full publication date if available
- Authors
-
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 Walz, Markus Gödel, Tobias B. HuberList of authors in order
- Landing page
-
https://doi.org/10.1681/asn.2016050519Publisher landing page
- PDF URL
-
https://jasn.asnjournals.org/content/jnephrol/28/7/2144.full.pdfDirect link to full text PDF
- Open access
-
YesWhether a free full text is available
- OA status
-
bronzeOpen access status per OpenAlex
- OA URL
-
https://jasn.asnjournals.org/content/jnephrol/28/7/2144.full.pdfDirect OA link when available
- Concepts
-
mTORC1, PI3K/AKT/mTOR pathway, Podocyte, Cancer research, Biology, Glomerulosclerosis, Cell biology, Endocrinology, Kidney, Signal transduction, ProteinuriaTop concepts (fields/topics) attached by OpenAlex
- Cited by
-
71Total citation count in OpenAlex
- Citations by year (recent)
-
2025: 8, 2024: 6, 2023: 6, 2022: 11, 2021: 12Per-year citation counts (last 5 years)
- References (count)
-
59Number of works referenced by this work
- Related works (count)
-
10Other works algorithmically related by OpenAlex
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| referenced_works | https://openalex.org/W2163543028, https://openalex.org/W2089391563, https://openalex.org/W2171653925, https://openalex.org/W1981066251, https://openalex.org/W1968216888, https://openalex.org/W2033910236, https://openalex.org/W6674597436, https://openalex.org/W2170453602, https://openalex.org/W2145225947, https://openalex.org/W2319567010, https://openalex.org/W2033798110, https://openalex.org/W2051719011, https://openalex.org/W2314456704, https://openalex.org/W2127063807, https://openalex.org/W2023012828, https://openalex.org/W2041308494, https://openalex.org/W2002226709, https://openalex.org/W2097243879, https://openalex.org/W2100150669, https://openalex.org/W1989100792, https://openalex.org/W1967468516, https://openalex.org/W2012783381, https://openalex.org/W2111820685, https://openalex.org/W6681691843, https://openalex.org/W2115134069, https://openalex.org/W1998740840, https://openalex.org/W2157230648, https://openalex.org/W2102989684, https://openalex.org/W2135900832, https://openalex.org/W2172163957, https://openalex.org/W1998399313, https://openalex.org/W2026210867, https://openalex.org/W2159116972, https://openalex.org/W2108217760, https://openalex.org/W7074041599, https://openalex.org/W2018676609, https://openalex.org/W2079244641, https://openalex.org/W2037233461, https://openalex.org/W2085804980, https://openalex.org/W2021129026, https://openalex.org/W2091510537, https://openalex.org/W2061031271, https://openalex.org/W2149282639, https://openalex.org/W2108586840, https://openalex.org/W2137571953, https://openalex.org/W2124802842, https://openalex.org/W1990488096, https://openalex.org/W2028031291, https://openalex.org/W2181477489, https://openalex.org/W2009598063, https://openalex.org/W2032823887, https://openalex.org/W2173187023, https://openalex.org/W2040757434, https://openalex.org/W2106875648, https://openalex.org/W2148924233, https://openalex.org/W119898361, https://openalex.org/W2147189605, https://openalex.org/W2915967003, https://openalex.org/W2169510669 |
| referenced_works_count | 59 |
| abstract_inverted_index.1 | 48 |
| abstract_inverted_index.a | 9, 23, 85, 90, 202, 215 |
| abstract_inverted_index.by | 107, 125, 192 |
| abstract_inverted_index.in | 8, 51, 68, 76, 154, 201 |
| abstract_inverted_index.is | 6, 189 |
| abstract_inverted_index.of | 2, 11, 36, 45, 66, 105, 110, 117, 134, 152, 165, 176 |
| abstract_inverted_index.to | 19, 28, 34, 61, 207 |
| abstract_inverted_index.we | 40 |
| abstract_inverted_index.and | 58, 84, 168, 187, 211 |
| abstract_inverted_index.for | 218 |
| abstract_inverted_index.led | 27 |
| abstract_inverted_index.one | 128 |
| abstract_inverted_index.the | 64, 102, 115, 132, 140, 158 |
| abstract_inverted_index.FSGS | 83, 87, 119 |
| abstract_inverted_index.both | 80, 111 |
| abstract_inverted_index.data | 182 |
| abstract_inverted_index.from | 32, 79 |
| abstract_inverted_index.just | 127 |
| abstract_inverted_index.loss | 188 |
| abstract_inverted_index.mTOR | 17, 46, 67, 153, 194, 197, 220 |
| abstract_inverted_index.role | 65 |
| abstract_inverted_index.that | 184 |
| abstract_inverted_index.thus | 213 |
| abstract_inverted_index.were | 73 |
| abstract_inverted_index.with | 21, 82, 93, 139, 173 |
| abstract_inverted_index.FSGS, | 22 |
| abstract_inverted_index.FSGS. | 69, 100 |
| abstract_inverted_index.Here, | 39 |
| abstract_inverted_index.genes | 72 |
| abstract_inverted_index.human | 59, 99 |
| abstract_inverted_index.model | 92 |
| abstract_inverted_index.mouse | 91 |
| abstract_inverted_index.rates | 164 |
| abstract_inverted_index.these | 181 |
| abstract_inverted_index.which | 171 |
| abstract_inverted_index.(mTOR) | 4 |
| abstract_inverted_index.Raptor | 112, 129 |
| abstract_inverted_index.allele | 130 |
| abstract_inverted_index.energy | 160 |
| abstract_inverted_index.injury | 186 |
| abstract_inverted_index.kidney | 12, 37 |
| abstract_inverted_index.levels | 50 |
| abstract_inverted_index.mTORC1 | 70, 95, 106, 123, 141 |
| abstract_inverted_index.model. | 88 |
| abstract_inverted_index.murine | 52, 86, 118 |
| abstract_inverted_index.oxygen | 178 |
| abstract_inverted_index.stress | 210 |
| abstract_inverted_index.target | 1, 71 |
| abstract_inverted_index.toward | 162 |
| abstract_inverted_index.trials | 15 |
| abstract_inverted_index.alleles | 113 |
| abstract_inverted_index.closely | 97 |
| abstract_inverted_index.complex | 42, 47 |
| abstract_inverted_index.disease | 54, 146 |
| abstract_inverted_index.genetic | 43 |
| abstract_inverted_index.induced | 75, 108 |
| abstract_inverted_index.leading | 206 |
| abstract_inverted_index.models, | 55 |
| abstract_inverted_index.models. | 120 |
| abstract_inverted_index.ranging | 31 |
| abstract_inverted_index.reduced | 163 |
| abstract_inverted_index.results | 200 |
| abstract_inverted_index.shifted | 157 |
| abstract_inverted_index.studies | 60 |
| abstract_inverted_index.suggest | 183 |
| abstract_inverted_index.variety | 10 |
| abstract_inverted_index.(mTORC1) | 49 |
| abstract_inverted_index.Clinical | 14 |
| abstract_inverted_index.However, | 121 |
| abstract_inverted_index.Notably, | 101 |
| abstract_inverted_index.adaptive | 193 |
| abstract_inverted_index.cellular | 159, 209 |
| abstract_inverted_index.combined | 41 |
| abstract_inverted_index.commonly | 190 |
| abstract_inverted_index.complete | 103, 149 |
| abstract_inverted_index.deleting | 126 |
| abstract_inverted_index.deletion | 109 |
| abstract_inverted_index.disease, | 26 |
| abstract_inverted_index.followed | 191 |
| abstract_inverted_index.however, | 199 |
| abstract_inverted_index.involved | 7 |
| abstract_inverted_index.knockout | 104 |
| abstract_inverted_index.low-dose | 137 |
| abstract_inverted_index.lowering | 122 |
| abstract_inverted_index.offering | 214 |
| abstract_inverted_index.patients | 20, 81 |
| abstract_inverted_index.podocyte | 25, 185, 204 |
| abstract_inverted_index.reactive | 177 |
| abstract_inverted_index.results, | 30 |
| abstract_inverted_index.species. | 179 |
| abstract_inverted_index.studies, | 57 |
| abstract_inverted_index.Mammalian | 0 |
| abstract_inverted_index.Prolonged | 196 |
| abstract_inverted_index.Together, | 180 |
| abstract_inverted_index.anaerobic | 169 |
| abstract_inverted_index.delineate | 63 |
| abstract_inverted_index.diseases. | 13 |
| abstract_inverted_index.function. | 38 |
| abstract_inverted_index.glomeruli | 78 |
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| abstract_inverted_index.inhibitor | 142 |
| abstract_inverted_index.metabolic | 203 |
| abstract_inverted_index.oxidative | 166 |
| abstract_inverted_index.podocytes | 156 |
| abstract_inverted_index.precisely | 62 |
| abstract_inverted_index.rapamycin | 3, 143 |
| abstract_inverted_index.rationale | 217 |
| abstract_inverted_index.remission | 33 |
| abstract_inverted_index.signaling | 5, 124 |
| abstract_inverted_index.titration | 44 |
| abstract_inverted_index.treatment | 138, 216 |
| abstract_inverted_index.Similarly, | 136 |
| abstract_inverted_index.activation | 96 |
| abstract_inverted_index.correlated | 172 |
| abstract_inverted_index.diminished | 145 |
| abstract_inverted_index.glomerular | 53 |
| abstract_inverted_index.incomplete | 219 |
| abstract_inverted_index.inhibition | 151 |
| abstract_inverted_index.inhibitors | 18 |
| abstract_inverted_index.metabolism | 161 |
| abstract_inverted_index.production | 175 |
| abstract_inverted_index.prototypic | 24 |
| abstract_inverted_index.accelerated | 114 |
| abstract_inverted_index.activation, | 198 |
| abstract_inverted_index.activation. | 195 |
| abstract_inverted_index.ameliorated | 131 |
| abstract_inverted_index.conflicting | 29 |
| abstract_inverted_index.efficiently | 144 |
| abstract_inverted_index.glycolysis, | 170 |
| abstract_inverted_index.inhibition. | 221 |
| abstract_inverted_index.progression | 116, 133 |
| abstract_inverted_index.Furthermore, | 89 |
| abstract_inverted_index.constitutive | 94 |
| abstract_inverted_index.immortalized | 155 |
| abstract_inverted_index.progression. | 147 |
| abstract_inverted_index.administering | 16 |
| abstract_inverted_index.deterioration | 35 |
| abstract_inverted_index.pharmacologic | 56, 150 |
| abstract_inverted_index.recapitulated | 98 |
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| abstract_inverted_index.significantly | 74 |
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| abstract_inverted_index.phosphorylation | 167 |
| abstract_inverted_index.Mechanistically, | 148 |
| abstract_inverted_index.dedifferentiation, | 212 |
| abstract_inverted_index.glomerulosclerosis. | 135 |
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| cited_by_percentile_year.min | 98 |
| corresponding_author_ids | https://openalex.org/A5082676002, https://openalex.org/A5107448068, https://openalex.org/A5083062387, https://openalex.org/A5101985529, https://openalex.org/A5034675493, https://openalex.org/A5076632645, https://openalex.org/A5063437346, https://openalex.org/A5041277413, https://openalex.org/A5068133416, https://openalex.org/A5015436238, https://openalex.org/A5085653275, https://openalex.org/A5075618597, https://openalex.org/A5112478490 |
| countries_distinct_count | 5 |
| institutions_distinct_count | 22 |
| corresponding_institution_ids | https://openalex.org/I159176309, https://openalex.org/I161046081, https://openalex.org/I37461747, https://openalex.org/I4210108711, https://openalex.org/I4210140357, https://openalex.org/I8204097 |
| citation_normalized_percentile.value | 0.95626228 |
| citation_normalized_percentile.is_in_top_1_percent | False |
| citation_normalized_percentile.is_in_top_10_percent | True |