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. 2019 Dec 19;4(1):bvz034.
doi: 10.1210/jendso/bvz034. eCollection 2020 Jan 1.

Glucagon-Like Peptide 1 and Atrial Natriuretic Peptide in a Female Mouse Model of Obstructive Pulmonary Disease

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Free PMC article

Glucagon-Like Peptide 1 and Atrial Natriuretic Peptide in a Female Mouse Model of Obstructive Pulmonary Disease

Emilie Balk-Møller et al. J Endocr Soc. .
Free PMC article

Abstract

Glucagon-like peptide-1 (GLP-1) is protective in lung disease models but the underlying mechanisms remain elusive. Because the hormone atrial natriuretic peptide (ANP) also has beneficial effects in lung disease, we hypothesized that GLP-1 effects may be mediated by ANP expression. To study this putative link, we used a mouse model of chronic obstructive pulmonary disease (COPD) and assessed lung function by unrestrained whole-body plethysmography. In 1 study, we investigated the role of endogenous GLP-1 by genetic GLP-1 receptor (GLP-1R) knockout (KO) and pharmaceutical blockade of the GLP-1R with the antagonist exendin-9 to -39 (EX-9). In another study the effects of exogenous GLP-1 were assessed. Lastly, we investigated the bronchodilatory properties of ANP and a GLP-1R agonist on isolated bronchial sections from healthy and COPD mice. Lung function did not differ between mice receiving phosphate-buffered saline (PBS) and EX-9 or between GLP-1R KO mice and their wild-type littermates. The COPD mice receiving GLP-1R agonist improved pulmonary function (P < .01) with less inflammation, but no less emphysema compared to PBS-treated mice. Compared with the PBS-treated mice, treatment with GLP-1 agonist increased ANP (nppa) gene expression by 10-fold (P < .01) and decreased endothelin-1 (P < .01), a peptide associated with bronchoconstriction. ANP had moderate bronchodilatory effects in isolated bronchial sections and GLP-1R agonist also showed bronchodilatory properties but less than ANP. Responses to both peptides were significantly increased in COPD mice (P < .05, P < .01). Taken together, our study suggests a link between GLP-1 and ANP in COPD.

Keywords: Glucagon-like peptide-1; atrial natriuretic peptide; inflammation; lung disease; whole-body plethysmography.

Figures

Figure 1.
Figure 1.
Validation of KO mouse strain and optimization of COPD model. A, Insulin secretion on GLP-1 stimulation by the pancreas using isolated pancreas perfusion. As opposed to the WT mice (black), the KO mice (green) do not respond to GLP-1. B, Immunohistochemical staining with GLP-1 R ab of pancreatic islets in (left) WT and (right) GLP-1R KO mice. Arrows point to pancreatic β cells in the islets of Langerhans but no immunoreaction in the GLP-1 R KO mouse. C, Comparison of responses to COPD-induction in BALB/c mice and C57BL/6JRj with and without sensitization with OVA pellets. D, Investigation of the duration and intensity of the response to COPD induction in C57BL/6JRj mice. Group 1 was measured from time 0 to 12 and 24 to 30 hours after the last LPS inhalation, and group 2 was measured from 12 to 24 hours.
Figure 2.
Figure 2.
Endogenous GLP-1 is not protective in COPD. Data are presented as time-effects plots from day 12 to 21 in the left panel. Right panel shows bar graphs at day 18, 12 hours after the last LPS inhalation. A, Study investigating the effect on PenH by antagonizing the GLP-1R with EX-9, n = 48. B, GLP-1R KO and WT, n = 30. Data are shown as means ± SEM. Statistics were carried out with 1-way ANOVA followed by Bonferroni post hoc test. **P < .01
Figure 3.
Figure 3.
Effect of liraglutide on histopathology and inflammatory markers in COPD. A, Bar graph of histopathological score in the different groups. H&E staining showing B, perivascular edema; C, perivascular/peribronchial acute inflammation; D, goblet cell metaplasia of the bronchioles; and E, macrophages/mononuclear cells in the alveolar spaces. F, Emphysema score. Examples of emphysema scored as G, mild; H, moderate; I, and severe. J, Healthy mouse lung for comparison. K, Measurements of proinflammatory cytokines in plasma from COPD mice. Comparisons were carried out between lira 12-h and PBS 12-h, lira 72 h and PBS 72 h. Data are shown as means ± SEM, n = 32. Statistics were analyzed by 1-way ANOVA followed by Bonferroni post hoc test. **P < .01.
Figure 4.
Figure 4.
Gene expression analysis. All genes were normalized to the housekeeping gene HPRT-1. A, ANP (nppa); B, ANPR-A (npr1); C, ANP clearance receptor, ANPR-C (npr3); and D, endothelin-1, ET-1 (edn1). E, Apelin (apl). F, E-selectin (sele). PBS healthy and lira healthy refer to animals treated for 10 days with liraglutide or PBS, but with no induction of COPD. Data are expressed as means ± SEM, n = 32. Statistics were analyzed using 1-way ANOVA followed by post hoc test comparing PBS and lira at 12 or 72 h *P < .05, **P < .01, ***P < .001.
Figure 5.
Figure 5.
ANP and EX-4 both exerted bronchodilating effects on isolated bronchi of mice. Concentration-relaxation curves induced by ANP and EX-4 on bronchial smooth muscle tissue. Values are expressed relative to the maximal effect of SNP (0.1 mM), which was added at the end of the experiment. Data are shown as means ± SEM. A, Relaxation induced by ANP (0.001-1 mM) in healthy mice. B, Relaxation induced by EX-4 (0.001-1 mM) in healthy mice. C, The effect of ANP on tissue from COPD mice compared to healthy mice. D, The effect of EX-4 on COPD compared to healthy mice. Data from A and B were analyzed by 1-way ANOVA followed by Bonferroni post hoc test comparing each concentration to 0.001 mM, which was considered as zero effect. Data from C and D were analyzed by 2-way ANOVA followed by Sidak post hoc test comparing the responses of COPD and healthy mice at each concentration. *P < .05, **P < .01.
Figure 6.
Figure 6.
Direct effects of ANP and Ex-4 on smooth muscles of isolated mouse bronchi, including nonresponders. Concentration-relaxation curves induced by ANP and EX-4 on bronchial smooth muscle tissue. Relaxation values are expressed as a percentage of the relaxation seen with a maximally effective concentration of SNP (0.1 mM) added at the end of the experiment. Data are shown as means ± SEM. A, The effect of ANP on tissue from COPD compared to healthy mice. B, The effect of EX-4 on COPD mice compared to healthy mice. C, Example of myograph signals from tissue sections responding to ANP and D, not responding to ANP, but to SNP.

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