Role of the prostaglandin E2/E-prostanoid 2 receptor signalling pathway in TGFβ-induced mice mesangial cell damage

• Published in: Bioscience reports 2014-12, Vol.34 (6), p.e00159-e00159
• Main Authors: Li, Na-Na, Xu, Yu-Yin, Chen, Xiao-Lan, Fan, Ya-Ping, Wu, Jian-Hua
• Format: Article
• Language: English
• Subjects: Adenoviruses; Animals; Blotting, Western; Cell growth; Cell Proliferation - drug effects; Cells, Cultured; Collagen (type I); Collagen Type I - genetics; Collagen Type I - metabolism; Connective tissue growth factor; Connective Tissue Growth Factor - genetics; Connective Tissue Growth Factor - metabolism; Connective tissues; Cyclic AMP; Cyclic AMP - metabolism; Cyclic AMP Response Element-Binding Protein - metabolism; Cyclin D1 - genetics; Cyclin D1 - metabolism; Cyclooxygenase 2 - genetics; Cyclooxygenase 2 - metabolism; Cyclooxygenase-2; Damage prevention; Dinoprostone - metabolism; Extracellular matrix; Extracellular signal-regulated kinase; Extracellular Signal-Regulated MAP Kinases - metabolism; Fibronectin; Gene Expression; Growth factors; Intramolecular Oxidoreductases - genetics; Intramolecular Oxidoreductases - metabolism; Kidney diseases; Kinases; MAP kinase; Mesangial cells; Mesangial Cells - drug effects; Mesangial Cells - metabolism; Mice, Inbred C57BL; Molecular modelling; Original Paper; p38 Mitogen-Activated Protein Kinases - metabolism; Phosphorylation; Primary Cell Culture; Prostaglandin E1; Prostaglandin E2; Prostaglandin-E synthase; Prostaglandin-E Synthases; Proteins; Receptors; Receptors, Prostaglandin E, EP2 Subtype - genetics; Receptors, Prostaglandin E, EP2 Subtype - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Signal Transduction; siRNA; Transforming Growth Factor beta - pharmacology; Transforming growth factor-b1
• ISSN: 0144-8463; 1573-4935
• DOI: 10.1042/BSR20140130

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.