title: The plant-derived glucocorticoid receptor agonist Endiandrin A acts as co-stimulator of colonic epithelial sodium channels (ENaC) via SGK-1 and MAPKs.
abstract: 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.
authors.affiliation: Department of Gastroenterology, Division of Nutritional Medicine, Charité, Campus Benjamin Franklin, Berlin, Germany.
authors.forename: Dana
authors.initials: D
authors.lastname: Kuntzsch
authors.forename: Theresa
authors.initials: T
authors.lastname: Bergann
authors.forename: Petra
authors.initials: P
authors.lastname: Dames
authors.forename: Anja
authors.initials: A
authors.lastname: Fromm
authors.forename: Michael
authors.initials: M
authors.lastname: Fromm
authors.forename: Rohan A
authors.initials: RA
authors.lastname: Davis
authors.forename: Matthias F
authors.initials: MF
authors.lastname: Melzig
authors.forename: Joerg D
authors.initials: JD
authors.lastname: Schulzke
mesh_terms: D000818:Animals; D003106:Colon / Q000378:metabolism*; D003503:Cyclobutanes / Q000737:chemistry / Q000494:pharmacology*; D003907:Dexamethasone / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D053503:Epithelial Sodium Channels / Q000378:metabolism*; D005938:Glucocorticoids / Q000494:pharmacology; D019073:HT29 Cells; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D007408:Intestinal Absorption / Q000187:drug effects; D019770:Lauraceae / Q000737:chemistry*; D017705:Lignans / Q000737:chemistry / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D011965:Receptors, Glucocorticoid / Q000819:agonists* / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D003503:Cyclobutanes; D003907:Dexamethasone; D053503:Epithelial Sodium Channels; D005938:Glucocorticoids; D017874:Immediate-Early Proteins; D017705:Lignans; D020928:Mitogen-Activated Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011965:Receptors, Glucocorticoid; D012964:Sodium; D000099184:Serum-Glucocorticoid Regulated Kinases; C522142:endiandrin A