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Cited by 126NF-κB Signaling PathwaysLiver physiology and pathologyChronic Kidney Disease and Diabetes

Hepatocyte Growth Factor Exerts Its Anti-Inflammatory Action by Disrupting Nuclear Factor-κB Signaling

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Giannopoulou, Myrto, Dai, Chunsun, Tan, Xiaoyue, Wen, Xiaoyan, Michalopoulos, George K., Liu, Youhua·2008·The American Journal of Pathology
DOI 10.2353/ajpath.2008.070583PMC PMC2438283
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Abstract

Renal inflammation, characterized by the influx of inflammatory cells, is believed to play a critical role in the initiation and progression of a wide range of chronic kidney diseases. Here, we show that hepatocyte growth factor (HGF) inhibited renal inflammation and proinflammatory chemokine expression by disrupting nuclear factor (NF)-kappaB signaling. In vivo, HGF gene delivery inhibited interstitial infiltration of inflammatory T cells and macrophages, and suppressed expression of both RANTES (regulated on activation, normal T cell expressed and secreted) and monocyte chemoattractant protein-1 in a mouse model of obstructive nephropathy. In vitro, HGF abolished RANTES induction in human kidney epithelial cells, which was dependent on NF-kappaB signaling. HGF did not significantly affect the phosphorylation or degradation of IkappaBalpha; it also did not influence the phosphorylation or nuclear translocation of p65 NF-kappaB. However, HGF prevented p65 NF-kappaB binding to its cognate cis-acting element in the RANTES promoter. HGF action was dependent on the activation of the phosphoinositide 3-kinase/Akt pathway, which led to the phosphorylation and inactivation of glycogen synthase kinase (GSK)-3beta. Suppression of GSK-3beta activity mimicked HGF and abolished RANTES expression, whereas ectopic expression of GSK-3beta restored RANTES induction. HGF also induced renal GSK-3beta phosphorylation and inactivation after obstructive injury in vivo. These observations suggest that HGF is a potent anti-inflammatory cytokine that inhibits renal inflammation by disrupting NF-kappaB signaling and may be a promising therapeutic agent for progressive renal diseases.

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Cited by

Sorted by citations

Authors
Giannopoulou, M., Dai, C., Tan, X., Wen, X., Michalopoulos, G. K., & Liu, Y.
Affiliations
University of Pittsburgh (US)
Corresponding author
Liu, Youhua
ORCID
Venue
The American Journal of Pathology
Publisher
Elsevier BV
Published
2008-07
Volume
173
Issue
1
Pages
30-41
ISSN
0002-9440 (ISSN-L)
DOI
10.2353/ajpath.2008.070583
PMC
PMC2438283
OpenAlex
W2080477580
Cited by
126
References
0
Citations by year
2026: 3 · 2025: 5 · 2024: 10 · 2023: 10 · 2022: 6 · 2021: 4 · 2020: 4 · 2019: 5 · 2018: 5 · 2017: 2 · 2016: 5 · 2015: 4 · 2014: 10 · 2013: 17 · 2012: 11
FWCI
2.85
Type
journal article
Language
en
Open access
Licence
Locations
  • American Journal Of Pathology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institutes of Health (DK061408, DK064005, DK054922)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
Keywords
hepatocyte growth factor, NF-κB signaling, renal inflammation, obstructive nephropathy, RANTES, MCP-1, chemokine expression, GSK3β, phosphoinositide 3-kinase/Akt pathway, anti-inflammatory cytokines, chronic kidney disease, renal epithelial cells, inflammatory cell infiltration
MeSH terms
Animals, Cells, Cultured, Chemotaxis, Leukocyte, Enzyme Activation, Enzyme-Linked Immunosorbent Assay, Fluorescent Antibody Technique, Humans, Immunohistochemistry, Inflammation, Kidney Diseases, Monocytes, T-Lymphocytes, Blotting, Western, Signal Transduction, NF-kappa B, Hepatocyte Growth Factor, Gene Transfer Techniques, Chemokine CCL2, Chemokine CCL5, Phosphatidylinositol 3-Kinases, eIF-2 Kinase, Reverse Transcriptase Polymerase Chain Reaction, Glycogen Synthase Kinase 3, Immunoprecipitation, Mice, Rats, I-kappa B Kinase

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