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

Morag K. Mansley, Stuart M. Wilson

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    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.

    Original languageEnglish
    Pages (from-to)1778-1792
    Number of pages15
    JournalBritish Journal of Pharmacology
    Volume161
    Issue number8
    DOIs
    Publication statusPublished - 2010

    Keywords

    • kinase inhibitors
    • PP242
    • TORIN1
    • serum and glucocorticoid-inducible protein kinase 1
    • phosphoinositide-3-kinase
    • epithelial Na+ channel
    • cortical collecting duct
    • STIMULATED SODIUM-TRANSPORT
    • PROTEIN-KINASE
    • A6 CELLS
    • COLLECTING DUCT
    • MTOR COMPLEX
    • INSULIN
    • SERUM
    • CHANNEL
    • SGK1
    • PHOSPHORYLATION

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