AGTR2 absence or antagonism prevents cystic fibrosis pulmonary manifestations

Autor: Garry R. Cutting, David E. Nethery, Mitchell L. Drumm, Eric Barbato, Neha Joshi, Paul Litman, Cara Campanaro, Abdus Sattar, Rebecca J. Darrah, Michael R. Knowles, Frank J. Jacono, Lisa J. Strug, Craig A. Hodges, Anna L. Mitchell, Harriet Corvol, Jennifer Frey
Přispěvatelé: Gestionnaire, Hal Sorbonne Université, Case Western Reserve University [Cleveland], Department of Medicine [Cleveland, OH, USA], Veterans Affairs Medical Center, Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Sorbonne Université (SU), Service de Pneumologie pédiatrique [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Johns Hopkins University School of Medicine [Baltimore], University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), The Hospital for sick children [Toronto] (SickKids), This work was supported by Cystic Fibrosis Foundation grants DARRAH17PO and DARRAH1610 (to RJD), as well as DRUMM15RO and DRUMM15R1 (to MLD), Gilead Sciences Research Scholars Program in Cystic Fibrosis award (to RJD), as well as VA Research Service BLR&D Merit Review Award I01BX000873 (to FJJ). 1R56HL136293-01 (to RJD) from NIH/NHLBI., Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP]
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Lung Diseases
Male
0301 basic medicine
Angiotensin signaling
Cystic Fibrosis
Pyridines
GWAS follow up
DNA Mutational Analysis
Genome-wide association study
Angiotensin II Type 2 Receptor Blockers
Gene mutation
Cystic fibrosis
[SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract
Pulmonary function testing
Mice
0302 clinical medicine
Medicine
Child
Lung
Mice
Knockout
Imidazoles
Forced Expiratory Flow Rates
3. Good health
Female
Pulmonary and Respiratory Medicine
Subset Analysis
Pulmonary function
Genotype
Locus (genetics)
Receptor
Angiotensin
Type 2
Article
03 medical and health sciences
Animals
Humans
Retrospective Studies
business.industry
DNA
medicine.disease
Mouse models of airway disease
Disease Models
Animal
030104 developmental biology
030228 respiratory system
Mutation
Pediatrics
Perinatology and Child Health
Immunology
[SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract
Type-2 Angiotensin II Receptor
business
Antagonism
Follow-Up Studies
Zdroj: Journal of Cystic Fibrosis
Journal of Cystic Fibrosis, 2019, 18 (1), pp.127-134. ⟨10.1016/j.jcf.2018.05.013⟩
Journal of Cystic Fibrosis, Elsevier, 2019, 18 (1), pp.127-134. ⟨10.1016/j.jcf.2018.05.013⟩
ISSN: 1569-1993
Popis: International audience; BACKGROUND: Pulmonary disease remains the primary cause of morbidity and mortality for individuals with cystic fibrosis (CF). Variants at a locus on the X-chromosome containing the type 2 angiotensin II receptor gene (AGTR2) were identified by a large GWAS as significantly associating with lung function in CF patients. We hypothesized that manipulating the angiotensin-signaling pathway may yield clinical benefit in CF.METHODS: Genetic subset analysis was conducted on a local CF cohort to extend the GWAS findings. Next, we evaluated pulmonary function in CF mice with a deleted AGTR2 gene, and in those who were given subcutaneous injections of PD123,319, a selective AGTR2 antagonist for 12 weeks beginning at weaning.RESULTS: The genetic subset analysis replicated the initial GWAS identified association, and confirmed the association of this locus with additional lung function parameters. Studies in genetically modified mice established that absence of the AGTR2 gene normalized pulmonary function indices in two independent CF mouse models. Further, we determined that pharmacologic antagonism of AGTR2 improved overall pulmonary function in CF mice to near wild-type levels.CONCLUSIONS: These results identify that reduced AGTR2 signaling is beneficial to CF lung function, and suggest the potential of manipulating the angiotensin-signaling pathway for treatment and/or prevention of CF pulmonary disease. Importantly, the beneficial effects were not CF gene mutation dependent, and were able to be reproduced with pharmacologic antagonism. As there are clinically approved drugs available to target the renin-angiotensin signaling system, these findings may be quickly translated to human clinical trials.
Databáze: OpenAIRE
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