Dysregulation of epithelial Na+ absorption induced by inhibition of the kinases TORC1 and TORC2

Morag K Mansley, Stuart M Wilson

Research output: Contribution to journalArticlepeer-review


BACKGROUND AND PURPOSE: Although the serum and glucocorticoid-inducible protein kinase 1 (SGK1) appears to be involved in controlling epithelial Na(+) absorption, its role in this physiologically important ion transport process is undefined. As SGK1 activity is dependent upon target of rapamycin complex 2 (TORC2)-catalysed phosphorylation of SGK1-Ser(422) , we have explored the effects of inhibiting TORC2 and/or TORC1 upon the hormonal control of Na(+) absorption.

EXPERIMENTAL APPROACH: Na(+) absorption was quantified electrometrically in mouse cortical collecting duct cells (mpkCCD) grown to confluence on permeable membranes. Kinase activities were assessed by monitoring endogenous protein phosphorylation, with or without TORC1/2 inhibitors (TORIN1 and PP242) and the TORC1 inhibitor: rapamycin.

KEY RESULTS: Inhibition of TORC1/2 (TORIN1, PP242) suppressed basal SGK1 activity, prevented insulin- and dexamethasone-induced SGK1 activation, and caused modest (10-20%) inhibition of basal Na(+) absorption and substantial (∼80%) inhibition of insulin/dexamethasone-induced Na(+) transport. Inhibition of TORC1 did not impair SGK1 activation or insulin-induced Na(+) transport, but did inhibit (∼80%) dexamethasone-induced Na(+) absorption. Arginine vasopressin stimulated Na(+) absorption via a TORC1/2-independent mechanism.

CONCLUSION AND IMPLICATIONS: Target of rapamycin complex 2, but not TORC1, is important to SGK1 activation. Signalling via phosphoinositide-3-kinase/TORC2/SGK1 can explain insulin-induced Na(+) absorption. TORC2, but not TORC1, is also involved in glucocorticoid-induced SGK1 activation but its role is permissive. Glucocorticoid-induced Na(+) transport displayed a requirement for TORC1 activity. Therefore, TORC1 and TORC2 contribute to the regulation of Na(+) absorption. Pharmacological manipulation of TORC1/2 signalling may provide novel therapies for Na(+)-sensitive hypertension.

Original languageEnglish
Pages (from-to)1778-92
Number of pages15
JournalBritish Journal of Pharmacology
Issue number8
Publication statusPublished - Dec 2010


  • Absorption
  • Aldosterone
  • Animals
  • Arginine Vasopressin
  • Cells, Cultured
  • Dexamethasone
  • Epithelial Cells
  • Immediate-Early Proteins
  • Insulin
  • Kidney Tubules, Collecting
  • Membrane Potentials
  • Mice
  • Naphthyridines
  • Phosphorylation
  • Protein-Serine-Threonine Kinases
  • Sirolimus
  • Sodium
  • Trans-Activators
  • Transcription Factors


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