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This Article Full Text Full Text (PDF) All Versions of this Article: 291/6/F1332    most recent 00131.2006v1 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 (1) 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 D₂ inhibits TGF-₁-induced epithelial-to-mesenchymal transition in MDCK cells

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

Submitted 17 April 2006 ; accepted in final form 7 August 2006

In a separate study, we identified PGE₂ as a potent inhibitor of TGF-₁-induced epithelial-mesenchymal transition (EMT) in cultured Madin-Darby canine kidney (MDCK) cells (Zhang A, Wang M-H, Dong Z, and Yang T. Am J Physiol Renal Physiol 291: F1323–F1331, 2006). This finding prompted us to examine the roles of other prostanoids: PGD₂, PGF₂, PGI₂, and thromboxane A₂ (TXA₂). Treatment with 10 ng/ml TGF-₁ for 3 days induced EMT as reflected by conversion to the spindle-like morphology, loss of E-cadherin, and activation of -smooth muscle actin (-SMA). Treatment with PGD₂ remarkably preserved the epithelial-like morphology, restored the expression of E-cadherin, and abolished the activation of -SMA. In contrast, PGF₂, carbocyclic thromboxane A₂, PGI₂ and its stable analog beraprost were without an effect. MDCK cells expressed DP₁ and DP₂ receptors; however, the effect of PGD₂ was neither prevented by DP₁ antagonist BW-A868C or DP₂ antagonist BAY-u3405 nor was mimicked by DP₁ agonist BW-245C. cAMP-elevating agents forskolin and 8-Br-cAMP blocked EMT. However, cAMP blockers H89 and Rp-cAMP failed to block the effect of PGD₂. PGD₂ did not seem to act via its metabolites as 15-deoxy-Delta(12,14)-prostaglandin J₂ (15d-PGJ₂) levels in the medium following incubation with 3 µM PGD₂ were well below the values predicted from the cross activity of the assay. Exposure to TGF-₁ induced a threefold increase in reactive oxygen species production that was completely abolished by PGD₂. We conclude that 1) PGD₂, but not PGI₂, PGF₂, and TXA₂ inhibit EMT, 2) PGD₂ inhibits EMT independently of DP₁ and DP₂ receptors, and 3) PGD₂ exhibits antioxidant property which may, in part, account for the antifibrotic action of this PG.

reactive oxygen species; transforming growth factor-₁; Madin-Darby canine kidney cells

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