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Am J Physiol Renal Physiol (August 8, 2006). doi:10.1152/ajprenal.00131.2006
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Submitted on April 17, 2006
Accepted on August 7, 2006

Prostaglandin D2 Inhibits TGF-{beta}1-induced Epithelial-to-Mesenchymal Transition in MDCK Cells

Aihua Zhang1, Zheng Dong2, and Tianxin Yang1*

1 Medicine, University of Utah and Veterans Affairs Medical Center, Salt Lake City, Utah, United States
2 Cellular Biology and Anatomy, Medical College of Georgia, United States; Medical Research Service, Veterans Affairs Medical Center, United States

* To whom correspondence should be addressed. E-mail: tianxin.yang{at}hsc.utah.edu.

In a separate study, we identified PGE2 as a potent inhibitor of TGF-{beta}1-induced epithelial-mesenchymal transition (EMT) in cultured Madin-Darby canine kidney (MDCK) cells. This finding prompted us to examine the roles of other prostanoids: PGD2, PGF2{alpha}, PGI2, and thromboxane A2 (TXA2). Treatment with 10 ng/ml TGF-{beta}1 for 3 days induced EMT as reflected by conversion to the spindle-like morphology, loss of E-cadherin, and activation of {alpha}-smooth muscle actin ({alpha}-SMA). Treatment with PGD2 remarkably preserved the epithelial-like morphology, restored the expression of E-cadherin, and abolished the activation of {alpha}-SMA. In contrast, PGF2{alpha}, 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 BW245C. 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-{beta}1 induced a three-fold increase in ROS production that was completely abolished by PGD2. We conclude that: 1) PGD2, but not PGI2, PGF2{alpha}, and TXA2 inhibit EMT; 2) PGD2 inhibits EMT independently of DP1 and DP2 receptors, and 3) PGD2 exhibits anti-oxidant property which may in part account for the anti-fibrotic action of this PG.




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