title: Role of the prostaglandin E2/E-prostanoid 2 receptor signalling pathway in TGFβ-induced mice mesangial cell damage.
abstract: The prostaglandin E2 receptor, EP2 (E-prostanoid 2), plays an important role in mice glomerular MCs (mesangial cells) damage induced by TGFβ1 (transforming growth factor-β1); however, the molecular mechanisms for this remain unknown. The present study examined the role of the EP2 signalling pathway in TGFβ1-induced MCs proliferation, ECM (extracellular matrix) accumulation and expression of PGES (prostaglandin E2 synthase). We generated primary mice MCs. Results showed MCs proliferation promoted by TGFβ1 were increased; however, the production of cAMP and PGE2 (prostaglandin E2) was decreased. EP2 deficiency in these MCs augmented FN (fibronectin), Col I (collagen type I), COX2 (cyclooxygenase-2), mPGES-1 (membrane-associated prostaglandin E1), CTGF (connective tissue growth factor) and CyclinD1 expression stimulated by TGFβ1. Silencing of EP2 also strengthened TGFβ1-induced p38MAPK (mitogen-activated protein kinase), ERK1/2 (extracellular-signal-regulated kinase 1/2) and CREB1 (cAMP responsive element-binding protein 1) phosphorylation. In contrast, Adenovirus-mediated EP2 overexpression reversed the effects of EP2-siRNA (small interfering RNA). Collectively, the investigation indicates that EP2 may block p38MAPK, ERK1/2 and CREB1 phosphorylation via activation of cAMP production and stimulation of PGE2 through EP2 receptors which prevent TGFβ1-induced MCs damage. Our findings also suggest that pharmacological targeting of EP2 receptors may provide new inroads to antagonize the damage induced by TGFβ1.
authors.affiliation: *Department of Nephrology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China.
authors.forename: Na-Na
authors.initials: NN
authors.lastname: Li
authors.affiliation: *Department of Nephrology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China.
authors.forename: Yu-Yin
authors.initials: YY
authors.lastname: Xu
authors.affiliation: *Department of Nephrology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China.
authors.forename: Xiao-Lan
authors.initials: XL
authors.lastname: Chen
authors.affiliation: *Department of Nephrology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China.
authors.forename: Ya-Ping
authors.initials: YP
authors.lastname: Fan
authors.affiliation: *Department of Nephrology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China.
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Wu
mesh_terms: D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015870:Gene Expression; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism; D050527:Mesangial Cells / Q000187:drug effects* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D061251:Primary Cell Culture; D000071876:Prostaglandin-E Synthases; D034622:RNA Interference; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C526318:CCN2 protein, mouse; D024042:Collagen Type I; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D058307:Receptors, Prostaglandin E, EP2 Subtype; D016212:Transforming Growth Factor beta; D019938:Cyclin D1; D055513:Connective Tissue Growth Factor; D000242:Cyclic AMP; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; D015232:Dinoprostone