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1 Nephrology, University of Utah and Veterans Affairs Medical Center, Salt Lake City, Utah, United States
2 Physiology, Medical College of Georgia, Augusta, Georgia, United States
3 Cellular Biology and Anatomy, Medical College of Georgia, Augusta, Georgia, United States
* To whom correspondence should be addressed. E-mail: tianxin.yang{at}hsc.utah.edu.
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 COX-2-derived PGE2 in regulation of EMT in cultured 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. Exposure of MDCK cells to 10 ng/ml TGF-1 for 48 hours induced EMT as evidenced by conversion to the spindle-like morphology, loss of E-cadherin, and activation of 
-smooth muscle actin (-SMA). 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 approximately 50% in the presence of a COX-2 inhibitor SC58635. Therefore, our data suggest that PGE2 inhibits EMT via cAMP-dependent inhibition of ROS production and COX-2-derived PGE2 partially accounts for the antifibrotic effect of HGF.
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