Investigating respiratory simplification caused by prenatal RAGE upregulation

• Published in: Physiology (Bethesda, Md.) Vol. 38; no. S1
• Main Authors: Clarke, Derek, Curtis, Katrina, Wendt, Ryan, Stapley, Brendan, Clark, Evan, Campbell, Kennedy, Black, Joe, Hill, Nate, Arroyo, Juan, Reynolds, Paul
• Format: Journal Article
• Language: English
• Published: 01.05.2023
• ISSN: 1548-9213; 1548-9221
• DOI: 10.1152/physiol.2023.38.S1.5730932

Abstract only Receptors for advanced glycation end-products (RAGE) are multi-ligand cell surface receptors of the immunoglobulin superfamily predominantly expressed by lung epithelium. Previous experiments showed that RAGE upregulation throughout pregnancy caused significant fetal lung hypoplasia via elevated apoptosis and misregulation of the transcription factors thyroid transcription factor 1 (TTF1) and forkhead box protein A2 (Fox-A2). Our current research focused on characterizing the contributors to these abnormalities. We confirmed poor development of murine lungs through a time course of RAGE upregulation from conception to sacrifice on embryonic day (E)15.5, E16.5, E17.5, E18.5, and specific upregulation from E15.5 to E18.5 only. H&E staining confirmed significant simplification. We hypothesized that this malformation was in part due to aberrant levels of inflammation and apoptosis. Blotting revealed significantly increased levels of phosphorylated AKT and ERK1/2 in RAGE TG pups which cause NF-κB mediated transcription of inflammatory genes. Due to potential roles for these signaling intermediates, we sought to assess RAGE-mediated impact on mitochondrial efficiency. Oxidative phosphorylation was assessed in lungs from RAGE TG pups and controls by measuring oxygen consumption per unit mass when lungs were exposed to the substrates malate, glutamate, ADP, succinate, and FCCP which activate sequential components of the electron transport chain. We discovered significantly increased levels of oxidative phosphorylation in transgenic pups compared to controls. Levels of ATP and reactive oxidative species (ROS) in relation to altered oxidative phosphorylation and inflammation provided additional mechanistic clarity. These results support the importance of proper RAGE regulation in the development of lung tissue and elucidate mechanisms possibly causing such damage. This work was supported by funding from the National Institutes of Health (NIH 1R15-HL152257, PRR and JAA). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.