Up-regulated expression of the receptor for advanced glycation end products in cultured rat hepatic stellate cells during transdifferentiation to myofibroblasts
Open accessAbstract
Receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily of cell-surface molecules. Blockade of RAGE has been reported to considerably improve liver function and accelerate regeneration after hepatectomy. The aim of this study was to investigate the cell type-specific expression of RAGE, and to examine whether transdifferentiation of hepatic stellate cells (HSC) into myofibroblasts (MFB) is associated with changes in RAGE expression. Northern blot analysis revealed that RAGE mRNA was exclusively expressed by HSC isolated from rat liver, while no transcripts were seen in hepatocytes, Kupffer cells, or sinusoidal endothelial cells. Expression of RAGE mRNA was up-regulated during transdifferentiation of HSC into MFB. Concomitantly, expression of RAGE protein was increased as confirmed by Western blotting and immunohistochemistry. As assessed by radioactive labeling, transforming growth factor β 1 (TGF-β 1) induced a time-dependent 2- to 15-fold increase in the de novo synthesis of RAGE protein, which was completely abolished using PD098059, a specific inhibitor of the mitogen-activated protein kinase (MAPK) kinase. As shown by double-immunofluorescence staining, RAGE colocalized with α-smooth muscle actin, and immunoelectron microscopy demonstrated the most prominent labeling for RAGE at filopodial membranes of MFB. In conclusion, this study demonstrates that expression of RAGE is restricted to rat HSC, and that expression is up-regulated during activation of HSC and transition to MFB. The preferential immunogold labeling of RAGE to focal membrane areas of filopodia of MFB is suggestive of a role of RAGE in the spreading and migration of activated HSC/MFB, major players in liver fibrogenesis.
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Accumulated AGEs and AGE-RAGE interactions in liver cells augment ROS generation and MAPK/NF-κB activation, leading to inflammatory cell death in the parenchyma and tissue remodeling during fibrosis.
“Accumulated AGEs and AGE-RAGE interactions in these cells augment the generation of ROS and the activation of MAPK and NF-κB pathways, leading to inflammatory cell death in the parenchyma and tissue remodeling processes during fibrosis127,128.”
From Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury (2021) · cites this paper as [127]
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- Authors
- Fehrenbach, H., Weiskirchen, R., Kasper, M., & Gressner, A. M.
- Affiliations
- University Hospital Carl Gustav Carus (DE)
- Universitätsklinikum Aachen (DE)
- Technische Universität Dresden (DE)
- Corresponding author
- Fehrenbach, Heinz
- Venue
- Hepatology
- Published
- 2001-11
- Volume
- 34
- Issue
- 5
- Pages
- 943-952
- ISSN
- 0270-9139 (ISSN-L)
- OpenAlex
- W2046392507
- Cited by
- 154
- References
- 57
- Citations by year
- 2025: 6 · 2024: 5 · 2023: 3 · 2022: 3 · 2021: 5 · 2020: 5 · 2019: 2 · 2018: 4 · 2017: 7 · 2016: 8 · 2015: 6 · 2014: 6 · 2013: 4 · 2012: 6
- FWCI
- 3.97
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- RWTH Publications (RWTH Aachen) (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
- Health Sciences › Medicine › Rehabilitation › Wound Healing and Treatments
- Keywords
- receptor for advanced glycation end products, hepatic stellate cells, myofibroblasts, transdifferentiation, liver fibrosis, TGF-β1, MAPK kinase, alpha-smooth muscle actin, filopodia, cell migration
- MeSH terms
- Receptor for Advanced Glycation End Products, Animals, Cell Differentiation, Cells, Cultured, Enzyme Inhibitors, Fibroblasts, Flavonoids, Immunologic Techniques, Liver, Male, Muscle, Smooth, Receptors, Immunologic, Up-Regulation, Transforming Growth Factor beta, Rats, Sprague-Dawley, Mitogen-Activated Protein Kinase Kinases, Rats, Transforming Growth Factor beta1
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