TY - JOUR
T1 - Prostaglandin E2 is a potent inhibitor of epithelial-to- mesenchymal transition
T2 - Interaction with hepatocyte growth factor
AU - Zhang, Aihua
AU - Wang, Mong Heng
AU - Dong, Zheng
AU - Yang, Tianxin
PY - 2006
Y1 - 2006
N2 - 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-β1 (TGF-β1) 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-β1, 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-β1 for 72 h induced EMT as evidenced by conversion to the spindle-like morphology, loss of E-cadherin, and activation of α-smooth muscle actin. In contrast, treatment with 1 μM PGE 2 completely blocked EMT, associated with a significant elevation of intracellular cAMP and complete blockade of TGF-β1-induced oxidant production. cAMP-elevating agents, including 8-Br-cAMP, forskolin, and IBMX, inhibited EMT and associated oxidative stress induced by TGF-β1, 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.
AB - 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-β1 (TGF-β1) 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-β1, 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-β1 for 72 h induced EMT as evidenced by conversion to the spindle-like morphology, loss of E-cadherin, and activation of α-smooth muscle actin. In contrast, treatment with 1 μM PGE 2 completely blocked EMT, associated with a significant elevation of intracellular cAMP and complete blockade of TGF-β1-induced oxidant production. cAMP-elevating agents, including 8-Br-cAMP, forskolin, and IBMX, inhibited EMT and associated oxidative stress induced by TGF-β1, 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.
KW - End-stage renal disease
KW - Tubulointerstitial fibrosis
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UR - http://www.scopus.com/inward/citedby.url?scp=33845358419&partnerID=8YFLogxK
U2 - 10.1152/ajprenal.00480.2005
DO - 10.1152/ajprenal.00480.2005
M3 - Article
C2 - 16868306
AN - SCOPUS:33845358419
SN - 0363-6127
VL - 291
SP - F1323-F1331
JO - American Journal of Physiology - Renal Physiology
JF - American Journal of Physiology - Renal Physiology
IS - 6
ER -