Grahammer, F, Haenisch, N, Steinhardt, F, Sander, L, Roerden, M, Arnold, F, Cordts, T, Wanner, N, Reichardt, W, Kerjaschki, D, Ruegg, MA, Hall, MN, Moulin, P, Busch, H, Boerries, M, Walz, G, Artunc, F and Huber, TB (2014) mTORC1 maintains renal tubular homeostasis and is essential in response to ischemic stress. Proc Natl Acad Sci U S A.

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

Item Type:	Article
Additional Information:	NIBR author: Moulin, P institute: NIBR contributor address: Renal Division, University Medical Center Freiburg, 79106 Freiburg, Germany;Renal Division, University Hospital Tubingen, 72076 Tubingen, Germany;Renal Division, University Medical Center Freiburg, 79106 Freiburg, Germany;Renal Division, University Medical Center Freiburg, 79106 Freiburg, Germany;Renal Division, University Hospital Tubingen, 72076 Tubingen, Germany;Renal Division, University Medical Center Freiburg, 79106 Freiburg, Germany;Renal Division, University Medical Center Freiburg, 79106 Freiburg, Germany;Renal Division, University Medical Center Freiburg, 79106 Freiburg, Germany;Spemann Graduate School of Biology and Medicine,Faculty of BiologyDepartment of Medical Physics, University Medical Center Freiburg, 79106 Freiburg, Germany;Department of Pathology, University of Vienna, 1090 Vienna, Austria;Biozentrum Basel, University of Basel, 4056 Basel, Switzerland;Biozentrum Basel, University of Basel, 4056 Basel, Switzerland;Novartis Institutes for Biomedical Research, Preclinical Safety, Discovery and Investigative Safety, 4002 Basel, Switzerland;Institute of Molecular Medicine and Cell Research, andGerman Cancer Consortium, 69120 Heidelberg, Germany; andGerman Cancer Research Center, 69120 Heidelberg, GermanyInstitute of Molecular Medicine and Cell Research, andGerman Cancer Consortium, 69120 Heidelberg, Germany; andGerman Cancer Research Center, 69120 Heidelberg, GermanyRenal Division, University Medical Center Freiburg, 79106 Freiburg, Germany;Renal Division, University Hospital Tubingen, 72076 Tubingen, Germany;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
Date Deposited:	13 Oct 2015 13:12
Last Modified:	13 Oct 2015 13:12
URI:	https://oak.novartis.com/id/eprint/22750