Role of the serum and glucocorticoid inducible kinase SGK1 in glucocorticoid stimulation of gastric acid secretion

Abstract

Glucocorticoids stimulate gastric acid secretion, an effect favoring the development of peptic ulcers. Putative mechanisms involved include the serum- and glucocorticoid-inducible kinase (SGK1), which stimulates a variety of epithelial channels and transporters. The present study explored the contribution of SGK1 to effects of glucocorticoids on gastric acid secretion. In isolated gastric glands from gene-targeted mice lacking functional SGK1 (sgk1 (-/-)) and their wild-type littermates (sgk1 (+/+)), H(+)-secretion (DeltapH/min) was determined utilizing 2',7'-bis(carboxyethyl)-5(6)-carboxyfluorescein (BCECF)-fluorescence, SGK1 transcript levels by in situ hybdridization, and expression of KCNQ1 channels by immunohistochemistry and real-time polymerase chain reaction. SGK1 transcript levels were enhanced by a 4-day treatment with 10 mug/g body weight (BW)/day dexamethasone (DEX). Before treatment, DeltapH/min was similar in sgk1 (-/-) and sgk1 (+/+)mice. DEX increased DeltapH/min approximately fourfold in sgk1 (+/+)mice and approximately twofold in sgk1 (-/-)mice, effects abolished in the presence of K(+)/H(+)ATPase-inhibitor omeprazole (50 microM). Increase in local K(+) concentrations to 35 mM (replacing Na(+)) enhanced DeltapH/min, which could not be further stimulated by DEX and was not significantly different between sgk1 (-/-) and sgk1 (+/+)mice. Carbachol (100 microM) and forskolin (5 microM) stimulated gastric acid secretion to a similar extent in sgk1 (-/-) and sgk1 (+/+)mice. In conclusion, SGK1 is not required for basal and cyclic AMP-stimulated gastric H(+) secretion but participates in the stimulation of gastric H(+) secretion by glucocorticoids. The effects of glucocorticoids and SGK1 are not additive to an increase in extracellular K(+) concentration and may thus involve stimulation of K(+) channels.

PI3 Kinase and PDK1 in the Regulation of the Electrogenic Intestinal Dipeptide Transport

“…Experiments utilizing dual electrode voltage clamp in Xenopus oocytes disclosed the ability of the serum-and glucocorticoid-inducible kinase SGK1 to stimulate the PepT1 [7] and PepT2 transporter activity 716 [8]. SGK1 [9] was originally cloned as a glucocorticoidinducible gene [10] and was shown to mediate the stimulating effect of dexamethasone on several transport systems including gastric acid secretion [11], intestinal glucose transport [12], intestinal Na + /H + exchanger activity [12][13][14], and intestinal peptide transport [7]. Notably, lack of SGK1 did not affect the basal peptide transport but abrogated its stimulation by glucocortioids [7].…”

Annexin 7 in the Regulation of Gastric Acid Secretion

“…According to an earlier study [53], the stimulation of gastric acid secretion depends on the serum- and glucocorticoid-inducible kinase (SGK1), which is known to stimulate a variety of epithelial channels and transporters [71]. The difference between SGK1-deficient mice and their littermates was similarly abrogated in the presence of 35 mM K + [53].…”

“…The difference between SGK1-deficient mice and their littermates was similarly abrogated in the presence of 35 mM K + [53]. Future studies may disclose interactions of SGK1 and annexin 7-dependent signaling in the regulation of gastric acid secretion.…”

“…The channels [48,49,50,51] and thus gastric acid secretion [41,43,52] are stimulated by cAMP. Gastric acid secretion is further stimulated by glucocorticoids [53], which decrease prostaglandin formation by downregulating cyclooxygenase 2 [38]. Nothing is known about the involvement of annexins in the glucocorticoid-dependent regulation of gastric acid secretion.…”

A Phosphoinositide 3-Kinase (PI3K)-serum- and glucocorticoid-inducible Kinase 1 (SGK1) Pathway Promotes Kv7.1 Channel Surface Expression by Inhibiting Nedd4-2 Protein

“…SGK1 Inhibition Mimics the Effects of PI3K Inhibition-As mentioned above, interesting downstream partners of PI3K are the SGK1 and Akt kinases, which have been reported to up-regulate Kv7.1 currents (31,32,(45)(46)(47). To test for a possible involvement of the two kinases upon Kv7.1 localization, the effects of the inhibitors GSK650394 (SGK1) and Akt inhibitor IV (Akt) were examined.…”