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Dysregulation of epithelial Na + absorption induced by inhibition of the kinases TORC1 and TORC2
Author(s) -
Mansley Morag K,
Wilson Stuart M
Publication year - 2010
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2010.01003.x
Subject(s) - sgk1 , kinase , phosphorylation , endocrinology , chemistry , medicine , microbiology and biotechnology , biology , biochemistry
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.