The Plant-Derived Glucocorticoid Receptor Agonist Endiandrin A Acts as Co-Stimulator of Colonic Epithelial Sodium Channels (ENaC) via SGK-1 and MAPKs
| Autor: | Anja Fromm, Michael Fromm, Petra Dames, Joerg D. Schulzke, Dana Kuntzsch, Matthias F. Melzig, Rohan A. Davis, Theresa Bergann |
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| Rok vydání: | 2012 |
| Předmět: |
Epithelial sodium channel
Phytochemistry Anatomy and Physiology Phytopharmacology Biochemistry Dexamethasone Transactivation Glucocorticoid receptor Drug Discovery Receptor Multidisciplinary Kinase Electrophysiology Chemistry Medicine Mitogen-Activated Protein Kinases HT29 Cells Research Article Biotechnology Transcriptional Activation Drugs and Devices medicine.medical_specialty Drug Research and Development Colon MAP Kinase Signaling System Science Sodium p38 mitogen-activated protein kinases chemistry.chemical_element Gastroenterology and Hepatology Protein Serine-Threonine Kinases Biology Lignans Immediate early protein Immediate-Early Proteins Lauraceae Receptors Glucocorticoid Complementary and Alternative Medicine Internal medicine medicine Animals Humans Rats Wistar Epithelial Sodium Channels Glucocorticoids Nutrition Inflammation Inflammatory Bowel Disease Molecular biology Rats Enzyme Activation Endocrinology Intestinal Absorption chemistry Cyclobutanes |
| Zdroj: | PLoS ONE, Vol 7, Iss 11, p e49426 (2012) PLoS ONE |
| ISSN: | 1932-6203 |
| DOI: | 10.1371/journal.pone.0049426 |
| Popis: | In a search for secondary plant compounds that bind to the glucocorticoid receptor (GR), the cyclobutane lignan endiandrin A was discovered from the rainforest tree Endiandra anthropophagorum Domin. Our present study aims to characterize the effect of endiandrin A on GR-dependent induction of colonic sodium transport. The effect of endiandrin A was analyzed in GR-expressing colonic HT-29/B6 cells (HT-29/B6-GR). GR transactivation and subcellular localization were investigated by reporter gene assay and immunofluorescence. Epithelial sodium channel (ENaC) was analyzed by qRT-PCR and by measuring amiloride-sensitive short-circuit current (I(sc)) in Ussing chambers. Endiandrin A (End A) has been identified as GR receptor binder. However, it did not cause significant GR transactivation as pGRE-luciferase activity was only 7% of that of the maximum effect of dexamethasone. Interestingly, endiandrin A had a significant impact on dexamethasone-dependent sodium absorption in cells co-exposed to tumor necrosis factor (TNF)-α. This was in part due to up-regulation of β- and γ-ENaC subunit expression. Endiandrin A potentiated GR-mediated transcription by increasing GR protein expression and phosphorylation. It inhibited c-Jun N-terminal kinase (JNK) activation induced by dexamethasone and/or TNF-α and increased levels of GR localized to the nucleus. Additionally, endiandrin A increased the serum- and glucocorticoid-induced kinase (sgk)-1 via activation of p38. Finally, the regulation of ENaC function by endiandrin A was confirmed in rat native colon. In conclusion, endiandrin A potentiates glucocorticoid-driven activation of colonic epithelial sodium channels via JNK inhibition and p38 activation due to transcriptional up-regulation of β- and γ-ENaC-subunits along with induction of sgk-1. |
| Databáze: | OpenAIRE |
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