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A novel mechanism by which hepatocyte growth factor blocks tubular epithelial to mesenchymal transition.
J Am Soc Nephrol. 2005 Jan; 16(1):68-78.JA

Abstract

Hepatocyte growth factor (HGF) is a potent antifibrotic cytokine that blocks tubular epithelial to mesenchymal transition (EMT) induced by TGF-beta1. However, the underlying mechanism remains largely unknown. This study investigated the signaling events that lead to HGF blockade of the TGF-beta1-initiated EMT. Incubation of human kidney epithelial cells HKC with HGF only marginally affected the expression of TGF-beta1 and its type I and type II receptors, suggesting that disruption of TGF-beta1 signaling likely plays a critical role in mediating HGF inhibition of TGF-beta1 action. However, HGF neither affected TGF-beta1-induced Smad-2 phosphorylation and its subsequent nuclear translocation nor influenced the expression of inhibitory Smad-6 and -7 in tubular epithelial cells. HGF specifically induced the expression of Smad transcriptional co-repressor SnoN but not Ski and TG-interacting factor at both mRNA and protein levels in HKC cells. SnoN physically interacted with activated Smad-2 by forming transcriptionally inactive complex and overrode the profibrotic action of TGF-beta1. In vivo, HGF did not affect Smad-2 activation and its nuclear accumulation in tubular epithelium, but it restored SnoN protein abundance in the fibrotic kidney in obstructive nephropathy. Hence, HGF blocks EMT by antagonizing TGF-beta1's action via upregulating Smad transcriptional co-repressor SnoN expression. These findings not only identify a novel mode of interaction between the signals activated by HGF receptor tyrosine kinase and TGF-beta receptor serine/threonine kinases but also illustrate the feasibility of confining Smad activity as an effective strategy for blocking renal fibrosis.

Authors+Show Affiliations

Division of Cellular and Molecular Pathology, Department of Pathology, University of Pittsburgh School of Medicine, S-405 Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, PA 15261, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15537870

Citation

Yang, Junwei, et al. "A Novel Mechanism By Which Hepatocyte Growth Factor Blocks Tubular Epithelial to Mesenchymal Transition." Journal of the American Society of Nephrology : JASN, vol. 16, no. 1, 2005, pp. 68-78.
Yang J, Dai C, Liu Y. A novel mechanism by which hepatocyte growth factor blocks tubular epithelial to mesenchymal transition. J Am Soc Nephrol. 2005;16(1):68-78.
Yang, J., Dai, C., & Liu, Y. (2005). A novel mechanism by which hepatocyte growth factor blocks tubular epithelial to mesenchymal transition. Journal of the American Society of Nephrology : JASN, 16(1), 68-78.
Yang J, Dai C, Liu Y. A Novel Mechanism By Which Hepatocyte Growth Factor Blocks Tubular Epithelial to Mesenchymal Transition. J Am Soc Nephrol. 2005;16(1):68-78. PubMed PMID: 15537870.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A novel mechanism by which hepatocyte growth factor blocks tubular epithelial to mesenchymal transition. AU - Yang,Junwei, AU - Dai,Chunsun, AU - Liu,Youhua, Y1 - 2004/11/10/ PY - 2004/11/13/pubmed PY - 2005/6/23/medline PY - 2004/11/13/entrez SP - 68 EP - 78 JF - Journal of the American Society of Nephrology : JASN JO - J Am Soc Nephrol VL - 16 IS - 1 N2 - Hepatocyte growth factor (HGF) is a potent antifibrotic cytokine that blocks tubular epithelial to mesenchymal transition (EMT) induced by TGF-beta1. However, the underlying mechanism remains largely unknown. This study investigated the signaling events that lead to HGF blockade of the TGF-beta1-initiated EMT. Incubation of human kidney epithelial cells HKC with HGF only marginally affected the expression of TGF-beta1 and its type I and type II receptors, suggesting that disruption of TGF-beta1 signaling likely plays a critical role in mediating HGF inhibition of TGF-beta1 action. However, HGF neither affected TGF-beta1-induced Smad-2 phosphorylation and its subsequent nuclear translocation nor influenced the expression of inhibitory Smad-6 and -7 in tubular epithelial cells. HGF specifically induced the expression of Smad transcriptional co-repressor SnoN but not Ski and TG-interacting factor at both mRNA and protein levels in HKC cells. SnoN physically interacted with activated Smad-2 by forming transcriptionally inactive complex and overrode the profibrotic action of TGF-beta1. In vivo, HGF did not affect Smad-2 activation and its nuclear accumulation in tubular epithelium, but it restored SnoN protein abundance in the fibrotic kidney in obstructive nephropathy. Hence, HGF blocks EMT by antagonizing TGF-beta1's action via upregulating Smad transcriptional co-repressor SnoN expression. These findings not only identify a novel mode of interaction between the signals activated by HGF receptor tyrosine kinase and TGF-beta receptor serine/threonine kinases but also illustrate the feasibility of confining Smad activity as an effective strategy for blocking renal fibrosis. SN - 1046-6673 UR - https://www.unboundmedicine.com/medline/citation/15537870/A_novel_mechanism_by_which_hepatocyte_growth_factor_blocks_tubular_epithelial_to_mesenchymal_transition_ L2 - https://jasn.asnjournals.org/cgi/pmidlookup?view=long&pmid=15537870 DB - PRIME DP - Unbound Medicine ER -