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Proc Natl Acad Sci U S A. 2014 Jul 8;111(27):E2817-26. doi: 10.1073/pnas.1402352111. Epub 2014 Jun 23.

mTORC1 maintains renal tubular homeostasis and is essential in response to ischemic stress.

Author information

1
Renal Division, University Medical Center Freiburg, 79106 Freiburg, Germany;
2
Renal Division, University Hospital Tübingen, 72076 Tübingen, Germany;
3
Renal Division, University Medical Center Freiburg, 79106 Freiburg, Germany;Spemann Graduate School of Biology and Medicine,Faculty of Biology.
4
Department of Medical Physics, University Medical Center Freiburg, 79106 Freiburg, Germany;
5
Department of Pathology, University of Vienna, 1090 Vienna, Austria;
6
Biozentrum Basel, University of Basel, 4056 Basel, Switzerland;
7
Novartis Institutes for Biomedical Research, Preclinical Safety, Discovery and Investigative Safety, 4002 Basel, Switzerland;
8
Institute of Molecular Medicine and Cell Research, andGerman Cancer Consortium, 69120 Heidelberg, Germany; andGerman Cancer Research Center, 69120 Heidelberg, Germany.
9
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.

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.

KEYWORDS:

acute kidney injury; mTOR; mitochondrial biogenesis; tubular transport; urinary concentration mechanism

PMID:
24958889
PMCID:
PMC4103333
DOI:
10.1073/pnas.1402352111
[Indexed for MEDLINE]
Free PMC Article

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