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Inhibition of the receptor for advanced glycation end-products (RAGE) protects from secondhand smoke (SHS)-induced intrauterine growth restriction IUGR in mice

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Abstract

Intrauterine growth restriction (IUGR) is a disease affecting 10% of all pregnancies. IUGR is associated with maternal, fetal, or placental abnormalities. Studies investigating the effects of secondhand smoke (SHS) exposure and IUGR are limited. The receptor for advanced glycation end-products (RAGE) is a pro-inflammatory transmembrane receptor increased by SHS in the placenta. We tested the hypothesis that inhibition of RAGE during SHS exposure protects from smoke-induced IUGR. C57BL/6 mice were exposed to SHS or SHS + semi-synthetic glycosaminoglycan ethers (SAGEs) known to inhibit RAGE signaling. Trophoblast cells were treated with cigarette smoke extract (CSE) with or without SAGEs in order to address the effects of RAGE inhibition during trophoblast invasion in vitro. SHS-treated mice demonstrated a significant reduction in fetal weight (7.35-fold, P ≤ 0.0001) and placental weight (1.13-fold, P ≤ 0.0001) compared with controls. Mice co-treated with SHS and SAGEs were protected from SHS-induced fetal weights decreases. SHS treatment of C57BL/6 mice activated placental extracellular signal-regulated kinase (ERK) (3.0-fold, P ≤ 0.05), JNK (2.4-fold, P ≤ 0.05) and p38 (2.1-fold, P ≤ 0.05) and the expression of inflammatory mediators including TNF-α (1.34-fold, P ≤ 0.05) and IL-1β (1.03-fold, P ≤ 0.05). SHS-mediated activation of these molecules was reduced to basal levels when SAGE was co-administered. Invasion of trophoblast cells decreased 92% (P < 0.002) when treated with CSE and CSE-mediated invasion was completely reversed by SAGEs. We conclude that RAGE inhibition protects against fetal weight loss during SHS-induced IUGR. These studies provide insight into tobacco-mediated IUGR development and clarify avenues that may be helpful in the alleviation of placental complications.

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Acknowledgements

The authors would like to thank Dr. Glenn D. Prestwich from the University of Utah Medical Center for his donation of SAGEs. Additionally, we would like to thank the many undergraduate students from the combined laboratories of Drs. Juan A. Arroyo and Paul R. Reynolds for their vital support.

Funding

This study was supported in part by grant 7R00HD055054-06, a grant from the Flight Attendant’s Medical Research Institute (FAMRI) and by BYU Mentoring Environment Grants.

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Authors and Affiliations

  1. Lung and Placental Research Laboratory, Department of Physiology and Developmental Biology, Brigham Young University, 3052 LSB, Provo, UT, 84602, USA

    Joshua B. Lewis, Camilo Mejia, Clinton Jordan, Troy D. Monson, Jared S. Bodine, Todd M. Dunaway, Kaleb M. Egbert, Adam L. Lewis, Tanner J. Wright, K. Connor Ogden, Dallin S. Broberg, Parker D. Hall, Shawn M. Nelson, Kelsey M. Hirschi, Paul R. Reynolds & Juan A. Arroyo

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  1. Joshua B. Lewis
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  2. Camilo Mejia
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Correspondence to Juan A. Arroyo.

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Lewis, J.B., Mejia, C., Jordan, C. et al. Inhibition of the receptor for advanced glycation end-products (RAGE) protects from secondhand smoke (SHS)-induced intrauterine growth restriction IUGR in mice. Cell Tissue Res 370, 513–521 (2017). https://doi.org/10.1007/s00441-017-2691-z

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