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

Morag K. Mansley, Stuart M. Wilson*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)

Abstract

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)1778-1792
Number of pages15
JournalBritish Journal of Pharmacology
Volume161
Issue number8
DOIs
Publication statusPublished - 1 Dec 2010

Keywords

  • Cortical collecting duct
  • Epithelial Na channel
  • Kinase inhibitors
  • Phosphoinositide-3-kinase
  • PP242
  • Serum and glucocorticoid-inducibleprotein kinase 1
  • TORIN1

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