Sandu Ciprian, Artunc Ferruh, Grahammer Florian, Rotte Anand, Boini Krishna M, Friedrich Björn, Sandulache Diana, Metzger Marco, Just Lothar, Mack Andreas, Skutella Thomas, Rexhepaj Rexhep, Risler Teut, Wulff Peer, Kuhl Dietmar, Lang Florian
Department of Physiology, University of Tuebingen, Tübingen, Germany.
Pflugers Arch. 2007 Dec;455(3):493-503. doi: 10.1007/s00424-007-0305-4. Epub 2007 Jul 6.
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.
糖皮质激素会刺激胃酸分泌，这种作用有利于消化性溃疡的发展。涉及的可能机制包括血清和糖皮质激素诱导激酶（SGK1），它能刺激多种上皮通道和转运体。本研究探讨了SGK1在糖皮质激素对胃酸分泌影响中的作用。在来自缺乏功能性SGK1的基因靶向小鼠（sgk1(-/-)）及其野生型同窝小鼠（sgk1(+/+)）的分离胃腺中，利用2',7'-双（羧乙基）-5（6）-羧基荧光素（BCECF）荧光测定H⁺分泌（ΔpH/分钟），通过原位杂交测定SGK1转录水平，并通过免疫组织化学和实时聚合酶链反应测定KCNQ1通道的表达。用10μg/g体重（BW）/天的地塞米松（DEX）进行4天治疗可提高SGK1转录水平。治疗前，sgk1(-/-)和sgk1(+/+)小鼠的ΔpH/分钟相似。DEX使sgk1(+/+)小鼠的ΔpH/分钟增加约四倍，使sgk1(-/-)小鼠增加约两倍，在存在K⁺/H⁺ATP酶抑制剂奥美拉唑（50μM）时这些作用消失。将局部K⁺浓度增加到35mM（替代Na⁺）可提高ΔpH/分钟，DEX不能进一步刺激该值，且sgk1(-/-)和sgk1(+/+)小鼠之间无显著差异。卡巴胆碱（100μM）和福斯高林（5μM）在sgk1(-/-)和sgk1(+/+)小鼠中对胃酸分泌的刺激程度相似。总之，基础和环磷酸腺苷刺激的胃H⁺分泌不需要SGK1，但SGK1参与糖皮质激素对胃H⁺分泌的刺激。糖皮质激素和SGK1的作用对细胞外K⁺浓度的增加无累加效应，因此可能涉及对K⁺通道的刺激。
