Key result
Inhibition of SGK1 by GSK650394A suppressed insulin-induced Na(+) absorption in cortical collecting duct cells, demonstrating dependence on PI3K/SGK1 signaling.
Why the study?
Do nominally selective inhibitors of PI3K, SGK1, and PKB reduce insulin-induced Na+ absorption in cortical collecting duct cells?
Do nominally selective inhibitors of PI3K, SGK1, and PKB reduce insulin-induced Na+ absorption in cortical collecting duct cells?
Insulin-induced Na+ absorption in cortical collecting duct cells depends on PI3K/SGK1 signaling, and Akti-1/2 is not a selective PKB inhibitor.
SGK1 inhibition may alter renal Na+ handling in insulin states; leaves open clinical translation from cell models.
BACKGROUND AND PURPOSE: Insulin-induced Na(+) retention in the distal nephron may contribute to the development of oedema/hypertension in patients with type 2 diabetes. This response to insulin is usually attributed to phosphatidylinositol-3-kinase (PI3K)/serum and glucocorticoid-inducible kinase 1 (SGK1) but a role for protein kinase B (PKB) has been proposed. The present study therefore aimed to clarify the way in which insulin can evoke Na(+) retention. EXPERIMENTAL APPROACH: We examined the effects of nominally selective inhibitors of PI3K (wortmannin, PI103, GDC-0941), SGK1 (GSK650394A) and PKB (Akti-1/2) on Na(+) transport in hormone-deprived and insulin-stimulated cortical collecting duct (mpkCCD) cells, while PI3K, SGK1 and PKB activities were assayed by monitoring the phosphorylation of endogenous proteins. KEY RESULTS: Wortmannin substantially inhibited basal Na(+) transport whereas PI103 and GDC-0941 had only very small effects. However, these PI3K inhibitors all abolished insulin-induced Na(+) absorption and inactivated PI3K, SGK1 and PKB fully. GSK650394A and Akti-1/2 also inhibited insulin-evoked Na(+) absorption and while GSK650394A inhibited SGK1 without affecting PKB, Akti-1/2 inactivated both kinases. CONCLUSION AND IMPLICATIONS: While studies undertaken using PI103 and GDC-0941 show that hormone-deprived cells can absorb Na(+) independently of PI3K, PI3K seems to be essential for insulin induced Na(+) transport. Akti-1/2 does not act as a selective inhibitor of PKB and data obtained using this compound must therefore be treated with caution. GSK650394A, on the other hand, selectively inhibits SGK1 and the finding that GSK650394A suppressed insulin-induced Na(+) absorption suggests that this response is dependent upon signalling via PI3K/SGK1.
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Mansley et al. (2010) studied this question. Kinase inhibitors (wortmannin, PI103, GDC-0941, GSK650394A, Akti-1/2) was evaluated on Na(+) transport and kinase phosphorylation. Inhibition of SGK1 by GSK650394A suppressed insulin-induced Na(+) absorption in cortical collecting duct cells, demonstrating dependence on PI3K/SGK1 signaling.
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