Bronchopulmonary dysplasia induced by hyperoxia attenuated by A GLP-1 analog, Liraglutide, by regulating the ACE-2/Ang(1-7)/Mas receptor pathway

Abstract

Background: Glucagon-like peptide-1 (GLP-1) shows promise for treating hyperoxia-induced bronchopulmonary dysplasia (BPD), but its mechanisms remain unclear. This study investigated the effects and potential mechanisms of GLP-1 using a hyperoxia-induced neonatal BPD mouse model.

Methods: Sprague-Dawley (SD) newborn rats were randomly assigned to four groups: control, hyperoxia, hyperoxia+Liraglutide, and hyperoxia+Liraglutide+A779. Lung tissues and bronchoalveolar lavage fluid (BALF) were collected at 3, 7, and 14 days post-exposure to air or hyperoxia. Hyperoxia-induced effects on lung development were assessed using haematoxylin and eosin staining. IL-6, TNF-α, and IL-1β levels in BALF were measured by ELISA. Expression of the ACE/AngII/AT1R and ACE-2/Ang(1-7)/Mas axes was analysed via reverse transcription-quantitative polymerase chain reaction (RT-qPCR), Western blotting, and immunohistochemistry.

Results: Hyperoxia-induced BPD rats exhibited abnormal alveolar structure, characterized by simplified architecture, thickened septa, and a dysregulated renin-angiotensin system (RAS). Liraglutide significantly reduced hyperoxia-induced levels of IL-1β, TNF-α, and IL-6 in BALF and improved alveolar architecture. Moreover, when comparing the BPD group with the BPD+Lira+A779 group, the BPD+Lira group showed a notable decrease in relative mRNA expression of ACE, AngII, and AT1R (P < 0.05), while mRNA levels of ACE-2 and Ang1 increased significantly (P < 0.05). Consistent with RT-PCR findings, western blot analysis demonstrated that, in the BPD+Lira group, protein levels of ACE and AngII in the lung tissue of neonatal rats significantly lower in the BPD + Liraglutide group at postnatal days 3, 7, and 14 compared to both the BPD and BPD+Liraglutide+A779 groups. Conversely, ACE-2 and Ang(1-7) protein concentrations were markedly elevated. These results suggested that liraglutide may protect against hyperoxia-induced neonatal BPD by suppressing the ACE/AngII/AT1R axis and activating ACE-2/Ang(1-7)/Mas axis, an effect antagonized by A779.

Conclusions: These findings elucidated a mechanism whereby GLP-1 mitigated hyperoxia-induced BPD through inhibition of the ACE/AngII/AT1R pathway and activation of the ACE-2/Ang(1-7)/Mas axis.

Impact: Liraglutide is capable to protect against hyperoxia-induced neonatal BPD in vitro. Liraglutide mitigated hyperoxia-induced BPD through inhibition of ACE/AngII/AT1R and activation of the ACE-2/Ang(1-7)/Mas axis. The ACE/AngII/AT1R and ACE-2/Ang(1-7)/Mas pathways could be one of those novel mechanisms for treating BPD.