Proceedings of the National Academy of Sciences of the United States of America · 2014
mTORC1 maintains renal tubular homeostasis and is essential in response to ischemic stress.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
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Grahammer Florian, Haenisch Nora, Steinhardt Frederic, Sandner Lukas, Roerden Malte, Arnold Frederic, Cordts Tomke, Wanner Nicola, Reichardt Wilfried, Kerjaschki Dontscho, Ruegg Markus A, Hall Michael N, Moulin Pierre, Busch Hauke, Boerries Melanie, Walz Gerd, Artunc Ferruh, Huber Tobias B
Аннотация
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.