mTORC2 critically regulates renal potassium handling

J Clin Invest. 2016 May 2;126(5):1773-82. doi: 10.1172/JCI80304. Epub 2016 Apr 4.

Abstract

The mTOR pathway orchestrates cellular homeostasis. The rapamycin-sensitive mTOR complex (mTORC1) in the kidney has been widely studied; however, mTORC2 function in renal tubules is poorly characterized. Here, we generated mice lacking mTORC2 in the distal tubule (Rictorfl/fl Ksp-Cre mice), which were viable and had no obvious phenotype, except for a 2.5-fold increase in plasma aldosterone. Challenged with a low-Na+ diet, these mice adequately reduced Na+ excretion; however, Rictorfl/fl Ksp-Cre mice rapidly developed hyperkalemia on a high-K+ diet, despite a 10-fold increase in serum aldosterone levels, implying that mTORC2 regulates kaliuresis. Phosphorylation of serum- and glucocorticoid-inducible kinase 1 (SGK1) and PKC-α was absent in Rictorfl/fl Ksp-Cre mice, indicating a functional block in K+ secretion activation via ROMK channels. Indeed, patch-clamp experiments on split-open tubular segments from the transition zone of the late connecting tubule and early cortical collecting duct demonstrated that Ba2+-sensitive apical K+ currents were barely detectable in the majority of Rictorfl/fl Ksp-Cre mice. Conversely, epithelial sodium channel (ENaC) activity was largely preserved, suggesting that the reduced ability to maintain K+ homeostasis is the result of impaired apical K+ conductance and not a reduced electrical driving force for K+ secretion. Thus, these data unravel a vital and nonredundant role of mTORC2 for distal tubular K+ handling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Hyperkalemia / genetics
  • Hyperkalemia / metabolism
  • Kidney Tubules / metabolism*
  • Mechanistic Target of Rapamycin Complex 2
  • Mice
  • Mice, Transgenic
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism*
  • Potassium / metabolism*
  • Potassium Channels, Inwardly Rectifying / genetics
  • Potassium Channels, Inwardly Rectifying / metabolism
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism*
  • Water-Electrolyte Balance / physiology*

Substances

  • Kcnj1 protein, mouse
  • Multiprotein Complexes
  • Potassium Channels, Inwardly Rectifying
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 2
  • Potassium