title: Prostaglandin E2 is a potent inhibitor of epithelial-to-mesenchymal transition: interaction with hepatocyte growth factor.
abstract: Epithelial-to-mesenchymal transition (EMT) has emerged as a critical event in the pathogenesis of tubulointerstitial fibrosis. EMT is typically induced by transforming growth factor-beta1 (TGF-beta1) and inhibited by hepatocyte growth factor (HGF). The present study was undertaken to evaluate the potential role of cyclooxygenase (COX)-2-derived PGE2 in regulation of EMT in cultured Madin-Darby canine kidney (MDCK) cells, in the setting of HGF treatment. Exposure to 50 ng/ml HGF significantly induced COX-2 protein expression and PGE2 release, whereas other growth factors, including epidermal growth factor, the insulin-like growth factor I protein, platelet-derived growth factor-BB, and TGF-beta1, had no effects on COX-2 expression or PGE2 release. COX-2 induction by HGF was preceded by activation of ERK1/2, and an ERK1/2-specific inhibitor, U-0126 (10 microM), completely abolished HGF-induced COX-2 expression. Exposure of MDCK cells to 10 ng/ml TGF-beta1 for 72 h induced EMT as evidenced by conversion to the spindle-like morphology, loss of E-cadherin, and activation of alpha-smooth muscle actin. In contrast, treatment with 1 microM PGE2 completely blocked EMT, associated with a significant elevation of intracellular cAMP and complete blockade of TGF-beta1-induced oxidant production. cAMP-elevating agents, including 8-Br-cAMP, forskolin, and IBMX, inhibited EMT and associated oxidative stress induced by TGF-beta1, but inhibition of cAMP pathway with Rp-cAMP, the cAMP analog, and H89, the protein kinase A (PKA) inhibitor, did not block the effect of PGE2. The effect of HGF on EMT was inhibited by approximately 50% in the presence of a COX-2 inhibitor SC-58635 (10 microM). Therefore, our data suggest that PGE2 inhibits EMT via inhibition of oxidant production and COX-2-derived PGE2 partially accounts for the antifibrotic effect of HGF.
authors.affiliation: Division of Nephrology, University of Utah and VA Medical Center, Salt Lake City, UT 84148, USA.
authors.forename: Aihua
authors.initials: A
authors.lastname: Zhang
authors.forename: Mong-Heng
authors.initials: MH
authors.lastname: Wang
authors.forename: Zheng
authors.initials: Z
authors.lastname: Dong
authors.forename: Tianxin
authors.initials: T
authors.lastname: Yang
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D015820:Cadherins / Q000378:metabolism; D000068579:Celecoxib; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism* / Q000494:pharmacology; D004285:Dogs; D004347:Drug Interactions; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D005355:Fibrosis; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D007676:Kidney Failure, Chronic / Q000378:metabolism / Q000473:pathology; D007684:Kidney Tubules / Q000473:pathology*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008648:Mesoderm / Q000378:metabolism / Q000473:pathology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
chemical_list: D000199:Actins; D015820:Cadherins; D016861:Cyclooxygenase Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D053773:Transforming Growth Factor beta1; D017228:Hepatocyte Growth Factor; D051546:Cyclooxygenase 2; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D000068579:Celecoxib; D015232:Dinoprostone