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This Article Full Text Full Text (PDF) All Versions of this Article: 291/6/F1323    most recent 00480.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (3) Citing Articles via Google Scholar Google Scholar Articles by Zhang, A. Articles by Yang, T. Search for Related Content PubMed PubMed Citation Articles by Zhang, A. Articles by Yang, T.

Prostaglandin E₂ is a potent inhibitor of epithelial-to-mesenchymal transition: interaction with hepatocyte growth factor

¹Division of Nephrology, University of Utah and Veterans Affairs Medical Center, Salt Lake City, Utah; and Departments of ²Physiology and ³Cellular Biology and Anatomy, Medical College of Georgia; and ⁴Medical Research Service, Veterans Affairs Medical Center, Augusta, Georgia

Submitted 1 December 2005 ; accepted in final form 3 July 2006

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-₁ (TGF-₁) 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-₁, 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 µM), completely abolished HGF-induced COX-2 expression. Exposure of MDCK cells to 10 ng/ml TGF-₁ for 72 h induced EMT as evidenced by conversion to the spindle-like morphology, loss of E-cadherin, and activation of -smooth muscle actin. In contrast, treatment with 1 µM PGE₂ completely blocked EMT, associated with a significant elevation of intracellular cAMP and complete blockade of TGF-₁-induced oxidant production. cAMP-elevating agents, including 8-Br-cAMP, forskolin, and IBMX, inhibited EMT and associated oxidative stress induced by TGF-₁, 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 50% in the presence of a COX-2 inhibitor SC-58635 (10 µM). 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.

tubulointerstitial fibrosis; end-stage renal disease

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