PPARγ agonists, such as pioglitazone, are widely used in the treatment of diabetes and several further disorders. They enhance transcription of the serum and glucocorticoid inducible kinase SGK1, which could in turn enhance gastric acid secretion by stimulating KCNQ1 K+ channels. The present study explored whether pioglitazone upregulates SGK1 protein expression in gastric glands and thus modifies gastric acid secretion. Food containing the PPARγ agonist pioglitazone (approximately 25mg/kg bw/day) was administered to gene-targeted mice lacking SGK1 (sgk1-/-, n=11) and their wild-type littermates (sgk1+/+, n=11). Western blotting was employed to analyze SGK1 expression, BCECF-fluorescence to determine acid secretion in isolated gastric glands and immunohistochemistry to elucidate KCNQ1 and H+/K+-ATPase protein abundance in the parietal cell membrane. Pioglitazone significantly increased SGK1 expression. Cytosolic pH and cellular buffer capacity were not significantly different between sgk1+/+ and sgk1-/- mice and not significantly modified in either genotype by pioglitazone. Without pioglitazone treatment, Na+-independent pH-recovery following an ammonium pulse (ΔpH/min) reflecting H+/K+-ATPase activity was again similar in sgk1+/+ and sgk1-/- mice. Pioglitazone significantly increased ΔpH/min (≈3 fold) in sgk1+/+ but not in sgk1-/- mice. H+/K+-ATPase inhibitor omeprazole (100 μM) abolished ΔpH/min in both genotypes irrespective of pioglitazone treatment. Increase in local K+ concentrations to 35 mM (replacing Na+/NMDG) significantly increased ΔpH/min and abrogated the differences between genotypes. KCNQ1 and H+/K+-ATPase protein abundance in the parietal cell membrane was enhanced by pioglitazone treatment in sgk1+/+ but not in sgk1-/- mice. In conclusion, pioglitazone increases gastric acid secretion, an effect at least partially due to stimulation of SGK1 expression and SGK1-dependent upregulation of KCNQ1.

Keywords:
Serum and glucocorticoid inducible kinase, SGK1, Omeprazole, H+/K+-ATPase, KCNQ1, PPARγ agonists
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© 2009 S. Karger AG, Basel
2009
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