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

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

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Authors

  • Morag K. Mansley
  • Stuart M. Wilson

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Info

Original languageEnglish
Pages1778-1792
Number of pages15
JournalBritish Journal of Pharmacology
Journal publication date2010
Volume161
Issue8
DOIs
StatePublished

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 (similar to 80%) inhibition of insulin/dexamethasone-induced Na+ transport. Inhibition of TORC1 did not impair SGK1 activation or insulin-induced Na+ transport, but did inhibit (similar to 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.

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