title: mTORC1 maintains renal tubular homeostasis and is essential in response to ischemic stress.
abstract: Mammalian target of rapamycin complex 1 (mTORC1) is a key regulator of cell metabolism and autophagy. Despite widespread clinical use of mTORC1 inhibitors, the role of mTORC1 in renal tubular function and kidney homeostasis remains elusive. By using constitutive and inducible deletion of conditional Raptor alleles in renal tubular epithelial cells, we discovered that mTORC1 deficiency caused a marked concentrating defect, loss of tubular cells, and slowly progressive renal fibrosis. Transcriptional profiling revealed that mTORC1 maintains renal tubular homeostasis by controlling mitochondrial metabolism and biogenesis as well as transcellular transport processes involved in countercurrent multiplication and urine concentration. Although mTORC2 partially compensated for the loss of mTORC1, exposure to ischemia and reperfusion injury exaggerated the tubular damage in mTORC1-deficient mice and caused pronounced apoptosis, diminished proliferation rates, and delayed recovery. These findings identify mTORC1 as an important regulator of tubular energy metabolism and as a crucial component of ischemic stress responses.
authors: Renal Division, University Medical Center Freiburg, 79106 Freiburg, Germany;
authors: Florian
authors: F
authors: Grahammer
authors: Renal Division, University Hospital Tübingen, 72076 Tübingen, Germany;
authors: Nora
authors: N
authors: Haenisch
authors: Renal Division, University Medical Center Freiburg, 79106 Freiburg, Germany;
authors: Frederic
authors: F
authors: Steinhardt
authors: Lukas
authors: L
authors: Sandner
authors: Renal Division, University Medical Center Freiburg, 79106 Freiburg, Germany;
authors: Lukas
authors: L
authors: Sander
authors: Renal Division, University Hospital Tübingen, 72076 Tübingen, Germany;
authors: Malte
authors: M
authors: Roerden
authors: Renal Division, University Medical Center Freiburg, 79106 Freiburg, Germany;
authors: Frederic
authors: F
authors: Arnold
authors: Renal Division, University Medical Center Freiburg, 79106 Freiburg, Germany;
authors: Tomke
authors: T
authors: Cordts
authors: Renal Division, University Medical Center Freiburg, 79106 Freiburg, Germany;Spemann Graduate School of Biology and Medicine,Faculty of Biology.
authors: Nicola
authors: N
authors: Wanner
authors: Department of Medical Physics, University Medical Center Freiburg, 79106 Freiburg, Germany;
authors: Wilfried
authors: W
authors: Reichardt
authors: Department of Pathology, University of Vienna, 1090 Vienna, Austria;
authors: Dontscho
authors: D
authors: Kerjaschki
authors: Biozentrum Basel, University of Basel, 4056 Basel, Switzerland;
authors: Markus A
authors: MA
authors: Ruegg
authors: Biozentrum Basel, University of Basel, 4056 Basel, Switzerland;
authors: Michael N
authors: MN
authors: Hall
authors: Novartis Institutes for Biomedical Research, Preclinical Safety, Discovery and Investigative Safety, 4002 Basel, Switzerland;
authors: Pierre
authors: P
authors: Moulin
authors: Institute of Molecular Medicine and Cell Research, andGerman Cancer Consortium, 69120 Heidelberg, Germany; andGerman Cancer Research Center, 69120 Heidelberg, Germany.
authors: Hauke
authors: H
authors: Busch
authors: Institute of Molecular Medicine and Cell Research, andGerman Cancer Consortium, 69120 Heidelberg, Germany; andGerman Cancer Research Center, 69120 Heidelberg, Germany.
authors: Melanie
authors: M
authors: Boerries
authors: Renal Division, University Medical Center Freiburg, 79106 Freiburg, Germany;
authors: Gerd
authors: G
authors: Walz
authors: Renal Division, University Hospital Tübingen, 72076 Tübingen, Germany;
authors: Ferruh
authors: F
authors: Artunc
authors: Renal Division, University Medical Center Freiburg, 79106 Freiburg, Germany;Spemann Graduate School of Biology and Medicine,Centre for Biological Signalling Studies, Albert Ludwigs University of Freiburg, 79104 Freiburg, Germany; tobias.huber@uniklinik-freiburg.de.
authors: Tobias B
authors: TB
authors: Huber
mesh_terms: D000818:Animals; D015153:Blotting, Western; D006706:Homeostasis / Q000502:physiology*; D007511:Ischemia / Q000503:physiopathology*; D007684:Kidney Tubules / Q000098:blood supply / Q000502:physiology*; D008279:Magnetic Resonance Imaging; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000235:genetics / Q000502:physiology*; D011141:Polyuria / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic
chemical_list: D046912:Multiprotein Complexes; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
keywords: acute kidney injury; mTOR; mitochondrial biogenesis; tubular transport; urinary concentration mechanism