title: A maladaptive role for EP4 receptors in mouse mesangial cells.
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 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-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.
authors.affiliation: Department of Nephrology, Affiliated Hospital of Nantong university, Nantong, Jiangsu, China; Department of Rheumatology, Affiliated Hospital of Jiangnan University (Wuxi 4th People's Hospital), Wuxi, Jiangsu, China.
authors.forename: Guang-xia
authors.initials: GX
authors.lastname: Yang
authors.affiliation: Department of Nephrology, Affiliated Hospital of Nantong university, Nantong, Jiangsu, China.
authors.forename: Yu-yin
authors.initials: YY
authors.lastname: Xu
authors.affiliation: Department of Nephrology, Affiliated Hospital of Nantong university, Nantong, Jiangsu, China.
authors.forename: Ya-ping
authors.initials: YP
authors.lastname: Fan
authors.affiliation: Shanghai Jiaotong University, School of Medicine, Shanghai, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Nephrology, Affiliated Hospital of Nantong university, Nantong, Jiangsu, China.
authors.forename: Xiao-lan
authors.initials: XL
authors.lastname: Chen
authors.affiliation: Department of Nephrology, Affiliated Hospital of Nantong university, Nantong, Jiangsu, China.
authors.forename: Yi-de
authors.initials: YD
authors.lastname: Zhang
authors.affiliation: Department of Nephrology, Affiliated Hospital of Nantong university, Nantong, Jiangsu, China.
authors.forename: Jian-hua
authors.initials: JH
authors.lastname: Wu
mesh_terms: D000419:Albuminuria / Q000378:metabolism; D000818:Animals; D001806:Blood Urea Nitrogen; D003404:Creatinine / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D007674:Kidney Diseases / Q000378:metabolism; D007678:Kidney Glomerulus / Q000378:metabolism; D008297:Male; D050527:Mesangial Cells / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009392:Nephrectomy / Q000379:methods; D009997:Osmotic Pressure / Q000502:physiology; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D058309:Receptors, Prostaglandin E, EP4 Subtype; D053773:Transforming Growth Factor beta1; D003404:Creatinine; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D015232:Dinoprostone