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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Homeostasis / physiology*
  • Ischemia / physiopathology*
  • Kidney Tubules / blood supply
  • Kidney Tubules / physiology*
  • Magnetic Resonance Imaging
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / physiology*
  • Polyuria / genetics
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / physiology*
  • Transcription, Genetic

Substances

  • Multiprotein Complexes
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1

Associated data

  • GEO/GSE54417