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Published on: January 16, 2015
Availability of Receptors for Advanced Glycation End-Products (RAGE) Influences Differential Transcriptome Expression
Katrina L Curtis1, Ashley Chang1, Ryan Van Slooten1
1Lung and Placenta Laboratory, Department of Cell Biology and Physiology, Brigham Young University, Provo, UT 84602, USA.
Abstract:
The receptor for advanced glycation end-products (RAGE) has a central function in orchestrating inflammatory responses in multiple disease states including chronic obstructive pulmonary disease (COPD). RAGE is a transmembrane pattern recognition receptor with particular interest in lung disease due to its naturally abundant pulmonary expression. Our previous research demonstrated an inflammatory role for RAGE following acute exposure to secondhand smoke (SHS). However, chronic inflammatory mechanisms associated with RAGE remain ambiguous. In this study, we assessed transcriptional outcomes in mice exposed to chronic SHS in the context of RAGE expression. RAGE knockout (RKO) and wild-type (WT) mice were delivered nose-only SHS via an exposure system for six months and compared to control mice exposed to room air (RA). We specifically compared WT + RA, WT + SHS, RKO + RA, and RKO + SHS. Analysis of gene expression data from WT + RA vs. WT + SHS showed FEZ1, Slpi, and Msln as significant at the three-month time point; while RKO + SHS vs. WT + SHS identified cytochrome p450 1a1 and Slc26a4 as significant at multiple time points; and the RKO + SHS vs. WT + RA revealed Tmem151A as significant at the three-month time point as well as Gprc5a and Dynlt1b as significant at the three- and six-month time points. Notable gene clusters were functionally analyzed and discovered to be specific to cytoskeletal elements, inflammatory signaling, lipogenesis, and ciliogenesis. We found gene ontologies (GO) demonstrated significant biological pathways differentially impacted by the presence of RAGE. We also observed evidence that the PI3K-Akt and NF-κB signaling pathways were significantly enriched in DEGs across multiple comparisons. These data collectively identify several opportunities to further dissect RAGE signaling in the context of SHS exposure and foreshadow possible therapeutic modalities.
Insights
Chronic secondhand smoke (SHS) exposure activates inflammatory pathways, with the receptor for advanced glycation end-products (RAGE) playing a key role in lung inflammation. This study identifies RAGE-dependent transcriptional changes in mice exposed to SHS.
Area of Science:
- Pulmonary Medicine
- Molecular Biology
- Toxicology
Background:
- The receptor for advanced glycation end-products (RAGE) is implicated in inflammatory responses, particularly in lung diseases like COPD.
- RAGE's role in chronic inflammation from secondhand smoke (SHS) exposure is not fully understood.
- Previous studies indicated RAGE's involvement in acute SHS exposure.
Purpose of the Study:
- To investigate the transcriptional changes associated with chronic SHS exposure in mice with and without RAGE.
- To elucidate the specific role of RAGE in mediating inflammatory and cellular responses to long-term SHS.
- To identify potential therapeutic targets for SHS-induced lung inflammation.
Main Methods:
- Mice (RAGE knockout and wild-type) were exposed to SHS or room air (RA) for six months.
- Gene expression analysis was performed at three and six months.
- Differential gene expression and pathway analysis (GO, PI3K-Akt, NF-κB) were conducted.
Main Results:
- Chronic SHS exposure induced significant transcriptional changes in wild-type mice, affecting genes related to inflammation and cellular structure.
- RAGE knockout mice showed distinct gene expression patterns compared to wild-type mice under SHS exposure.
- Key pathways, including PI3K-Akt and NF-κB signaling, were significantly enriched in differentially expressed genes, highlighting RAGE's influence.
Conclusions:
- RAGE signaling is a critical mediator of transcriptional responses to chronic SHS exposure in the lungs.
- Specific genes and pathways regulated by RAGE offer potential targets for therapeutic intervention.
- Further research into RAGE-dependent mechanisms can inform strategies to mitigate SHS-induced lung damage.
