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

Respiratory Research

Paul R Reynolds¹  Jeffrey A Stogsdill¹  Adam B Robinson¹  Zac R Jergensen¹  Alex J Wright¹  Alexander J Geyer¹  Benjamin R Bukey¹  Nicholas T Ferguson¹  Duane R Winden¹ 

[1] Department of Physiology and Developmental Biology, Brigham Young University, 375A Widtsoe Building, 84602 Provo, UT, USA

关键词: Collagen;    Lung;    Endothelium;    Transgenic;    RAGE;   

Others  :  792537
DOI  :  10.1186/1465-9921-14-108

 received in 2013-08-14, accepted in 2013-10-10,  发布年份 2013

【 摘 要 】

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.

【 授权许可】

   
2013 Winden et al.; licensee BioMed Central Ltd.

【 图 表 】

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