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AGTR2 absence or antagonism prevents cystic fibrosis pulmonary manifestations.

ABSTRACT: 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.

SUBMITTER: Darrah RJ

PROVIDER: S-EPMC6830504 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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AGTR2 absence or antagonism prevents cystic fibrosis pulmonary manifestations.

Darrah Rebecca J RJ Jacono Frank J FJ Joshi Neha N Mitchell Anna L AL Sattar Abdus A Campanaro Cara K CK Litman Paul P Frey Jennifer J Nethery David E DE Barbato Eric S ES Hodges Craig A CA Corvol Harriet H Cutting Garry R GR Knowles Michael R MR Strug Lisa J LJ Drumm Mitchell L ML

Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society 20180622 1

<h4>Background</h4>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.<h4>Methods</h4>Genetic subset analysis was conducted on a local CF coh ...[more]

PMID: 29937318

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AGTR2 absence or antagonism prevents cystic fibrosis pulmonary manifestations.

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AGTR2 absence or antagonism prevents cystic fibrosis pulmonary manifestations.

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