Identification of Impacted Pathways and Transcriptomic Markers as Potential Mediators of Pulmonary Fibrosis in Transgenic Mice Expressing Human IGFBP5

Pulmonary fibrosis is a serious disease characterized by extracellular matrix (ECM) component overproduction and remodeling. Insulin-like growth factor-binding protein 5 (IGFBP5) is a conserved member of the IGFBP family of proteins that is overexpressed in fibrotic tissues and promotes fibrosis. We...

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Autores principales: Xinh-Xinh Nguyen, Ludivine Renaud, Carol Feghali-Bostwick
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Publicado: MDPI AG 2021
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spelling oai:doaj.org-article:c5a6d2ee7b824825a1564a8dc271b74b2021-11-25T17:58:17ZIdentification of Impacted Pathways and Transcriptomic Markers as Potential Mediators of Pulmonary Fibrosis in Transgenic Mice Expressing Human IGFBP510.3390/ijms2222126091422-00671661-6596https://doaj.org/article/c5a6d2ee7b824825a1564a8dc271b74b2021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/22/12609https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Pulmonary fibrosis is a serious disease characterized by extracellular matrix (ECM) component overproduction and remodeling. Insulin-like growth factor-binding protein 5 (IGFBP5) is a conserved member of the IGFBP family of proteins that is overexpressed in fibrotic tissues and promotes fibrosis. We used RNA sequencing (RNAseq) to identify differentially expressed genes (DEGs) between primary lung fibroblasts (pFBs) of homozygous (HOMO) transgenic mice expressing human IGFBP5 (hIGFBP5) and wild type mice (WT). The results of the differential expression analysis showed 2819 DEGs in hIGFBP5 pFBs. Functional enrichment analysis confirmed the pro-fibrotic character of IGFBP5 and revealed its impact on fundamental signaling pathways, including cytokine–cytokine receptor interaction, focal adhesion, AGE-RAGE signaling, calcium signaling, and neuroactive ligand-receptor interactions, to name a few. Noticeably, 7% of the DEGs in hIGFBP5-expressing pFBs are receptors and integrins. Furthermore, hub gene analysis revealed 12 hub genes including Fpr1, Bdkrb2, Mchr1, Nmur1, Cnr2, P2ry14, and Ptger3. Validation assays were performed to complement the RNAseq data. They confirmed significant differences in the levels of the corresponding proteins in cultured pFBs. Our study provides new insights into the molecular mechanism(s) of IGFBP5-associated pulmonary fibrosis through possible receptor interactions that drive fibrosis and tissue remodeling.Xinh-Xinh NguyenLudivine RenaudCarol Feghali-BostwickMDPI AGarticleinsulin-like growth factor protein-5 (IGFBP5)transgenic modelG-protein-coupled receptor (GPCR)neuroactive ligand receptorfibrosistransmembrane receptorsBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 12609, p 12609 (2021)
institution DOAJ
collection DOAJ
language EN
topic insulin-like growth factor protein-5 (IGFBP5)
transgenic model
G-protein-coupled receptor (GPCR)
neuroactive ligand receptor
fibrosis
transmembrane receptors
Biology (General)
QH301-705.5
Chemistry
QD1-999
spellingShingle insulin-like growth factor protein-5 (IGFBP5)
transgenic model
G-protein-coupled receptor (GPCR)
neuroactive ligand receptor
fibrosis
transmembrane receptors
Biology (General)
QH301-705.5
Chemistry
QD1-999
Xinh-Xinh Nguyen
Ludivine Renaud
Carol Feghali-Bostwick
Identification of Impacted Pathways and Transcriptomic Markers as Potential Mediators of Pulmonary Fibrosis in Transgenic Mice Expressing Human IGFBP5
description Pulmonary fibrosis is a serious disease characterized by extracellular matrix (ECM) component overproduction and remodeling. Insulin-like growth factor-binding protein 5 (IGFBP5) is a conserved member of the IGFBP family of proteins that is overexpressed in fibrotic tissues and promotes fibrosis. We used RNA sequencing (RNAseq) to identify differentially expressed genes (DEGs) between primary lung fibroblasts (pFBs) of homozygous (HOMO) transgenic mice expressing human IGFBP5 (hIGFBP5) and wild type mice (WT). The results of the differential expression analysis showed 2819 DEGs in hIGFBP5 pFBs. Functional enrichment analysis confirmed the pro-fibrotic character of IGFBP5 and revealed its impact on fundamental signaling pathways, including cytokine–cytokine receptor interaction, focal adhesion, AGE-RAGE signaling, calcium signaling, and neuroactive ligand-receptor interactions, to name a few. Noticeably, 7% of the DEGs in hIGFBP5-expressing pFBs are receptors and integrins. Furthermore, hub gene analysis revealed 12 hub genes including Fpr1, Bdkrb2, Mchr1, Nmur1, Cnr2, P2ry14, and Ptger3. Validation assays were performed to complement the RNAseq data. They confirmed significant differences in the levels of the corresponding proteins in cultured pFBs. Our study provides new insights into the molecular mechanism(s) of IGFBP5-associated pulmonary fibrosis through possible receptor interactions that drive fibrosis and tissue remodeling.
format article
author Xinh-Xinh Nguyen
Ludivine Renaud
Carol Feghali-Bostwick
author_facet Xinh-Xinh Nguyen
Ludivine Renaud
Carol Feghali-Bostwick
author_sort Xinh-Xinh Nguyen
title Identification of Impacted Pathways and Transcriptomic Markers as Potential Mediators of Pulmonary Fibrosis in Transgenic Mice Expressing Human IGFBP5
title_short Identification of Impacted Pathways and Transcriptomic Markers as Potential Mediators of Pulmonary Fibrosis in Transgenic Mice Expressing Human IGFBP5
title_full Identification of Impacted Pathways and Transcriptomic Markers as Potential Mediators of Pulmonary Fibrosis in Transgenic Mice Expressing Human IGFBP5
title_fullStr Identification of Impacted Pathways and Transcriptomic Markers as Potential Mediators of Pulmonary Fibrosis in Transgenic Mice Expressing Human IGFBP5
title_full_unstemmed Identification of Impacted Pathways and Transcriptomic Markers as Potential Mediators of Pulmonary Fibrosis in Transgenic Mice Expressing Human IGFBP5
title_sort identification of impacted pathways and transcriptomic markers as potential mediators of pulmonary fibrosis in transgenic mice expressing human igfbp5
publisher MDPI AG
publishDate 2021
url https://doaj.org/article/c5a6d2ee7b824825a1564a8dc271b74b
work_keys_str_mv AT xinhxinhnguyen identificationofimpactedpathwaysandtranscriptomicmarkersaspotentialmediatorsofpulmonaryfibrosisintransgenicmiceexpressinghumanigfbp5
AT ludivinerenaud identificationofimpactedpathwaysandtranscriptomicmarkersaspotentialmediatorsofpulmonaryfibrosisintransgenicmiceexpressinghumanigfbp5
AT carolfeghalibostwick identificationofimpactedpathwaysandtranscriptomicmarkersaspotentialmediatorsofpulmonaryfibrosisintransgenicmiceexpressinghumanigfbp5
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