Dataset Information

Conditional over-expression of RAGE by embryonic alveolar epithelium compromises the respiratory membrane and impairs endothelial cell differentiation.

ABSTRACT:

Background

Receptors for advanced glycation end-products (RAGE) are cell surface receptors prominently expressed by lung epithelium. Previous research demonstrated that over-expression of RAGE by murine alveolar epithelial cells during embryogenesis caused severe lung hypoplasia and neonatal lethality. However, the effects of RAGE over-expression on adjacent matrix and endothelial cells remained unknown.

Methods

RAGE transgenic (TG) mice were generated that conditionally over-expressed RAGE in alveolar type II cells when fed doxycycline (dox) from conception to E18.5. To evaluate effects on the basement membrane, immunostaining and immunoblotting were performed for collagen IV and MMP-9, a matrix metalloprotease capable of degrading basement membranes. To assess changes in vasculature, immunostaining, immunoblotting and qRT-PCR were performed for Pecam-1, a platelet endothelial cell adhesion marker also known as CD31. Lastly, to characterize potential regulatory mechanisms of endothelial cell differentiation, immunoblotting and qRT-PCR for FoxM1, a key endothelium-specific transcription factor of the Forkhead Box (Fox) family, were completed.

Results

Qualitative immunostaining for collagen IV was less in RAGE TG mice compared to controls and immunoblotting revealed decreased collagen IV in the RAGE TG mouse lung. Additionally, elevated MMP-9 detected via immunostaining and immunoblotting implicated MMP-9 as a possible down stream effector in matrix destabilization mediated by RAGE signaling. Lastly, Pecam-1 assessment revealed a decrease in the prevalence of microvascular endothelial cells coincident with FoxM1 abrogation in RAGE TG mice compared to controls.

Conclusions

RAGE over-expression by alveolar epithelium weakened the basement membrane and associated matrix via increased MMP-9 activity. Furthermore, over-expression of RAGE inhibited FoxM1, suggesting that anomalous transcriptional control contributes to decreased endothelial cell prevalence in the TG mouse lung.

SUBMITTER: Winden DR

PROVIDER: S-EPMC3853184 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Publications

Conditional over-expression of RAGE by embryonic alveolar epithelium compromises the respiratory membrane and impairs endothelial cell differentiation.

Winden Duane R DR Ferguson Nicholas T NT Bukey Benjamin R BR Geyer Alexander J AJ Wright Alex J AJ Jergensen Zac R ZR Robinson Adam B AB Stogsdill Jeffrey A JA Reynolds Paul R PR

Respiratory research 20131017

<h4>Background</h4>Receptors for advanced glycation end-products (RAGE) are cell surface receptors prominently expressed by lung epithelium. Previous research demonstrated that over-expression of RAGE by murine alveolar epithelial cells during embryogenesis caused severe lung hypoplasia and neonatal lethality. However, the effects of RAGE over-expression on adjacent matrix and endothelial cells remained unknown.<h4>Methods</h4>RAGE transgenic (TG) mice were generated that conditionally over-expr ...[more]

PMID: 24134692

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Dataset Information

Conditional over-expression of RAGE by embryonic alveolar epithelium compromises the respiratory membrane and impairs endothelial cell differentiation.

Background

Methods

Results

Conclusions

Publications

Conditional over-expression of RAGE by embryonic alveolar epithelium compromises the respiratory membrane and impairs endothelial cell differentiation.

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