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

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.

A Role for RAGE in DNA Double Strand Breaks (DSBs) Detected in Pathological Placentas and Trophoblast Cells

“…The RAGE-ligand interaction is well-recognized for its modulation of chronic inflammatory diseases, such as type 2 diabetes, varieties of neurodegeneration, and chronic obstructive pulmonary disease [17,18]. More recently, our laboratory showed that increased placental expression of membrane bound RAGE contributes to low trophoblastic survival and insufficient invasion in a model of IUGR, suggesting a role of RAGE during placental disease [19]. Although membrane bound RAGE is predominately known for its function in inflammatory signaling, the nuclear isoform of RAGE (~64 kDa) was recently identified and demonstrated to be a positive regulator during DNA-DSB repair in the lungs via HRR.…”

Cell invasion, RAGE expression, and inflammation in oral squamous cell carcinoma (OSCC) cells exposed to e‐cigarette flavoring

“…Increased invasion induced by the flavoring alone was improved when 6 mg nicotine was included in the Red Hot flavoring (b). Invasion experiments were conducted with an n = 10 as outlined in the Methods section and statistically different values are noted as *p < .05 determine to what extent cytokine release was regulated by eCig treatment, we performed protein assays that simultaneously screened key inflammatory cytokines observed during periodontal disease and compared expression to cells exposed to CSE as a positive control (Lewis et al, 2017;Sanders et al, 2017). The concentration of IFN-γ, IL-1β, IL-12, IL-4, IL-6, IL-10, IL-12, IL-17, MIP1-α, MMP-9, Osteoprotegerin, Osteopontin, Osteoactivin, RANK, TGFβ1, and TNFα released into cell culture media was below the levels of detection; thus, we were not able to accurately determine their concentrations in the media from either control or treated cells.…”

Hyperlipidic diet affects body composition and induces anxiety‐like behaviour in intrauterine growth‐restricted adult mice

“…Considering the long‐term consequences of intrauterine growth restriction, many animal models have been used to simulate what is observed in humans, including the effects of restricted calories and proteins from the maternal diet, fetal hypoxia, passive smoking and hyperthermia (Barry et al., 2006; Ganguly, Touma, Thamotharan, De Vivo, & Devaskar, 2016; Lewis et al., 2017; Rueda‐Clausen et al., 2011). For instance, in rats, IUGR, produced by bilateral uterine artery ligation, was shown to determine glucose intolerance and insulin resistance at an early age, and marked elevation of glucose levels in 26‐week‐old offspring (Simmons, Templeton, & Gertz, 2001); maternal stress was also associated with IUGR and resulted in a long‐lasting disturbance in feeding behaviour and dysfunctions related to type 2 diabetes mellitus (Lesage et al., 2004).…”