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.