Rictor/mTORC2 protects against cisplatin-induced tubular cell death and acute kidney injury

Kidney Int. 2014 Jul;86(1):86-102. doi: 10.1038/ki.2013.559. Epub 2014 Jan 22.

Abstract

The mammalian target of rapamycin (mTOR) plays a critical role for cell growth and survival in many cell types. While substantial progress has been made in understanding the abnormal activation of mTORC1 in the pathogenesis of kidney disease, little is known about mTORC2 in kidney disease such as acute kidney injury (AKI). To study this, we generated a mouse model with tubule-specific deletion of Rictor (Tubule-Rictor-/-). The knockouts were born normal and no obvious kidney dysfunction or kidney morphologic abnormality was found within 2 months of birth. However, ablation of Rictor in the tubular cells exacerbated cisplatin-induced AKI compared to that in the control littermates. As expected, tubular cell apoptosis, Akt phosphorylation (Ser473), and autophagy were induced in the kidneys from the control littermates by cisplatin treatment. Less cell autophagy or Akt phosphorylation and more cell apoptosis in the kidneys of the knockout mice were identified compared with those in the control littermates. In NRK-52E cells in vitro, Rictor siRNA transfection sensitized cell apoptosis to cisplatin but with reduced cisplatin-induced autophagy. Metformin, an inducer of autophagy, abolished cell death induced by Rictor siRNA and cisplatin. Thus, endogenous Rictor/mTORC2 protects against cisplatin-induced AKI, probably mediated by promoting cell survival through Akt signaling activation and induction of autophagy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Kidney Injury / etiology
  • Acute Kidney Injury / metabolism
  • Acute Kidney Injury / prevention & control*
  • Animals
  • Apoptosis / drug effects
  • Autophagy / drug effects
  • Carrier Proteins / antagonists & inhibitors
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Survival / physiology
  • Cells, Cultured
  • Cisplatin / toxicity
  • Disease Models, Animal
  • Gene Knockdown Techniques
  • Kidney Tubules / drug effects
  • Kidney Tubules / metabolism*
  • Kidney Tubules / pathology
  • Male
  • Mechanistic Target of Rapamycin Complex 2
  • Metformin / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Multiprotein Complexes / deficiency
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA, Small Interfering / genetics
  • Rapamycin-Insensitive Companion of mTOR Protein
  • Signal Transduction
  • TOR Serine-Threonine Kinases / deficiency
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism*

Substances

  • Carrier Proteins
  • Multiprotein Complexes
  • RNA, Small Interfering
  • Rapamycin-Insensitive Companion of mTOR Protein
  • rictor protein, mouse
  • Metformin
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 2
  • Proto-Oncogene Proteins c-akt
  • Cisplatin