Prostaglandin E2 is a potent inhibitor of epithelial-to- mesenchymal transition: Interaction with hepatocyte growth factor

Aihua Zhang, Mong Heng Wang, Zheng Dong, Tianxin Yang

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54 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)F1323-F1331
JournalAmerican Journal of Physiology - Renal Physiology
Volume291
Issue number6
DOIs
StatePublished - Dec 14 2006

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Epithelial-Mesenchymal Transition
Hepatocyte Growth Factor
Dinoprostone
Cyclooxygenase 2
Transforming Growth Factors
Madin Darby Canine Kidney Cells
Celecoxib
Oxidants
1-Methyl-3-isobutylxanthine
Cyclooxygenase 2 Inhibitors
Colforsin
Cadherins
Protein Kinase Inhibitors
Cyclic AMP-Dependent Protein Kinases
Insulin-Like Growth Factor I
Epidermal Growth Factor
Smooth Muscle
Actins
Cultured Cells
Intercellular Signaling Peptides and Proteins

Keywords

  • End-stage renal disease
  • Tubulointerstitial fibrosis

ASJC Scopus subject areas

  • Physiology
  • Urology

Cite this

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title = "Prostaglandin E2 is a potent inhibitor of epithelial-to- mesenchymal transition: Interaction with hepatocyte growth factor",
abstract = "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.",
keywords = "End-stage renal disease, Tubulointerstitial fibrosis",
author = "Aihua Zhang and Wang, {Mong Heng} and Zheng Dong and Tianxin Yang",
year = "2006",
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doi = "10.1152/ajprenal.00480.2005",
language = "English (US)",
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pages = "F1323--F1331",
journal = "American Journal of Physiology - Heart and Circulatory Physiology",
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number = "6",

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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 - 2006/12/14

Y1 - 2006/12/14

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.

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