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

Florian Grahammer, Nora Haenisch, Frederic Steinhardt, Lukas Sandner, Lukas Sander, Malte Roerden, Frederic Arnold, Tomke Cordts, Nicola Wanner, Wilfried Reichardt, Dontscho Kerjaschki, Markus A Ruegg, Michael N Hall, Pierre Moulin, Hauke Busch, Melanie Boerries, Gerd Walz, Ferruh Artunc, Tobias B Huber


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.

Original languageEnglish
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number27
Pages (from-to)E2817-26
Publication statusPublished - 08.07.2014


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