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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Blotting, Western
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Cell Proliferation / drug effects
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Cells, Cultured
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Collagen Type I / genetics
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Collagen Type I / metabolism
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Connective Tissue Growth Factor / genetics
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Connective Tissue Growth Factor / metabolism
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Cyclic AMP / metabolism
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Cyclic AMP Response Element-Binding Protein / metabolism
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Cyclin D1 / genetics
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Cyclin D1 / metabolism
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Cyclooxygenase 2 / genetics
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Cyclooxygenase 2 / metabolism
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Dinoprostone / metabolism
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Gene Expression
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Intramolecular Oxidoreductases / genetics
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Intramolecular Oxidoreductases / metabolism
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Mesangial Cells / drug effects*
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Mesangial Cells / metabolism
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Mice, Inbred C57BL
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Phosphorylation
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Primary Cell Culture
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Prostaglandin-E Synthases
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RNA Interference
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Receptors, Prostaglandin E, EP2 Subtype / genetics
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Receptors, Prostaglandin E, EP2 Subtype / metabolism*
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction*
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Transforming Growth Factor beta / pharmacology*
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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CCN2 protein, mouse
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Collagen Type I
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Creb1 protein, mouse
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Cyclic AMP Response Element-Binding Protein
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Receptors, Prostaglandin E, EP2 Subtype
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Transforming Growth Factor beta
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Cyclin D1
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Connective Tissue Growth Factor
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Cyclic AMP
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Ptgs2 protein, mouse
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Cyclooxygenase 2
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Extracellular Signal-Regulated MAP Kinases
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p38 Mitogen-Activated Protein Kinases
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Intramolecular Oxidoreductases
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Prostaglandin-E Synthases
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Ptges protein, mouse
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Dinoprostone