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.
Highlights
The progression of chronic kidney disease (CKD) is characterized by glomerular hypertrophy, MC proliferation, extracellular matrix (ECM) accumulation, glomerulosclerosis and ESKD [1]
Primary mouse MCs were infected with AD-GFP or different concentration of AD-E-prostanoid 2 (EP2) (MOI = 0.5, 2.5, 5, 12.5) for 24 h and EP2 protein level was detected by Western blot analysis, β-actin was used as control. (A) Expression of EP2 in AD-EP2 infected MCs was detected by Western blot. (B) Quantification of EP2 expression is achieved using densitometric values normalized to β-actin levels
We found that EP2 – siRNA-transfected MCs have increased CREB phosphorylation compared with those of NC – siRNA-transfected MCs following TGFβ1 treatment (Figure 12A)
Summary
The progression of CKD (chronic kidney disease) is characterized by glomerular hypertrophy, MC (mesangial cell) proliferation, ECM (extracellular matrix) accumulation, glomerulosclerosis and ESKD (end-stage kidney disease) [1]. Central to the pathophysiology of CKD are the MCs. ECM is produced by damaged MCs and contains collagens type I, IV and V, laminin A, B1 and B2, FN and entactin, and nidogen. TGFβ has been recognized as a central player in many pathological events related to CKD progression at the glomerular, tubulointerstitial and vascular levels. Increased TGFβ expression in the obstructed kidney stimulates genes involved in ECM protein accumulation, including type 1 collagen and FN [3]. TGFβ stabilizes the ECM proteins by stimulating the expression of PAI-1 (plasminogen activator inhibitor 1). The inhibition of TGFβ signalling has been included in several therapeutic approaches for preventing renal fibrosis
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