| First Author | Yang GX | Year | 2014 |
| Journal | PLoS One | Volume | 9 |
| Issue | 8 | Pages | e104091 |
| PubMed ID | 25122504 | Mgi Jnum | J:223148 |
| Mgi Id | MGI:5648136 | Doi | 10.1371/journal.pone.0104091 |
| Citation | Yang GX, et al. (2014) A maladaptive role for EP4 receptors in mouse mesangial cells. PLoS One 9(8):e104091 |
| abstractText | Roles of the prostaglandin E2 E-prostanoid 4 receptor (EP4) on extracellular matrix (ECM) accumulation induced by TGF-beta1 in mouse glomerular mesangial cells (GMCs) remain unknown. Previously, we have identified that TGF-beta1 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 EP4(Flox/Flox) and EP4(+/-) mice, cultured primary WT, EP4(Flox/Flox) and EP4(+/-) GMCs, AD-EP4 transfected WT GMCs (EP4 overexpression) and AD-Cre transfected EP4(Flox/Flox) GMCs (EP4 deleted). We found that TGF-beta1-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-beta1 to FN, Col I expression and COX2/PGE2 signaling, while TGF-beta1 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-beta1 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. |
