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

MK Mansley, SM Wilson - British journal of pharmacology, 2010 - Wiley Online Library
MK Mansley, SM Wilson
British journal of pharmacology, 2010Wiley Online Library
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‐Ser422, we have explored the effects of inhibiting TORC2 and/or TORC1 upon the
hormonal control of Na+ absorption. EXPERIMENTAL APPROACH Na+ absorption was …
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‐Ser422, 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.
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