Abstract
Roles of the prostaglandin E2 E-prostanoid 4 receptor (EP4) on extracellular matrix (ECM) accumulation induced by TGF-β1 in mouse glomerular mesangial cells (GMCs) remain unknown. Previously, we have identified that TGF-β1 stimulates the expression of FN and Col I in mouse GMCs. Here we asked whether stimulation of EP4 receptors would exacerbate renal fibrosis associated with enhanced glomerular ECM accumulation. We generated EP4Flox/Flox and EP4+/− mice, cultured primary WT, EP4Flox/Flox and EP4+/− GMCs, AD-EP4 transfected WT GMCs (EP4 overexpression) and AD-Cre transfected EP4Flox/Flox GMCs (EP4 deleted). We found that TGF-β1-induced cAMP and PGE2 synthesis decreased in EP4 deleted GMCs and increased in EP4 overexpressed GMCs. Elevated EP4 expression in GMCs augmented the coupling of TGF-β1 to FN, Col I expression and COX2/PGE2 signaling, while TGF-β1 induced FN, Col I expression and COX2/PGE2 signaling were down-regulated in EP4 deficiency GMCs. 8 weeks after 5/6 nephrectomy (Nx), WT and EP4+/− mice exhibited markedly increased accumulation of ECM compared with sham-operated controls. Albuminuria, blood urea nitrogen and creatinine (BUN and Cr) concentrations were significantly increased in WT mice as compared to those of EP4+/− mice. Urine osmotic pressure was dramatically decreased after 5/6 Nx surgery in WT mice as compared to EP4+/− mice. The pathological changes in kidney of EP4+/− mice was markedly alleviated compared with WT mice. Immunohistochemical analysis showed significant reductions of Col I and FN in the kidney of EP4+/− mice compared with WT mice. Collectively, this investigation established EP4 as a potent mediator of the pro-TGF-β1 activities elicited by COX2/PGE2 in mice GMCs. Our findings suggested that prostaglandin E2, acting via EP4 receptors contributed to accumulation of ECM in GMCs and promoted renal fibrosis.
Highlights
Renal fibrosis is the underlying pathological alteration and the common way of almost all progressive kidney diseases
The purpose of the present work was to research the impact of E-prostanoid 4 receptor (EP4) expression on TGF-b1 induced extracellular matrix (ECM) accumulation of mouse glomerular mesangial cells (GMCs), and investigate renal pathological changes in EP4+/2 mice after 5/6 Nx to explore the possible mechanisms involved in kidney fibrosis induced by EP4 activation
We investigated the impact of EP4 receptor deletion from the GMCs on renal fibrosis
Summary
Renal fibrosis is the underlying pathological alteration and the common way of almost all progressive kidney diseases. The ECM is mainly produced by mesangial cells (MCs) and contains collagens type I, IV and V, laminin A, B1 and B2, fibronectin, heparan sulfate and chondroitin sulfate proteoglycans, entactin, nidogen and etc. ECM is the major factor of mesangial expansion as seen in many glomerular diseases associated with increased synthesis in the MCs [2]. MCs play a critical role in initiation of glomerular inflammation and progression to chronic kidney disease. TGF-b plays an essential role in MCs hypertrophy associated with diabetes and other glomerulopathies [3] through CTGF-mediated mechanism [4]. Enhanced expression of the TGF-b1 gene is one of the most permanent molecular changes causing pathological tissue fibrosis [5]
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