AGTR2 absence or antagonism prevents cystic fibrosis pulmonary manifestations

Rebecca J. Darrah, Frank J. Jacono, Neha Joshi, Anna L. Mitchell, Abdus Sattar, Cara K. Campanaro, Paul Litman, Jennifer Frey, David E. Nethery, Eric S. Barbato, Craig A. Hodges, Harriet Corvol, Garry R Cutting, Michael R. Knowles, Lisa J. Strug, Mitchell L. Drumm

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalJournal of Cystic Fibrosis
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Cystic Fibrosis
Lung
Genome-Wide Association Study
Angiotensins
Lung Diseases
Genes
Angiotensin Receptors
Chromosomes, Human, Pair 2
X Chromosome
Subcutaneous Injections
Renin-Angiotensin System
Weaning
Clinical Trials
Morbidity
Mutation
Mortality

Keywords

  • Angiotensin signaling
  • GWAS follow up
  • Mouse models of airway disease
  • Pulmonary function

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Pulmonary and Respiratory Medicine

Cite this

Darrah, R. J., Jacono, F. J., Joshi, N., Mitchell, A. L., Sattar, A., Campanaro, C. K., ... Drumm, M. L. (Accepted/In press). AGTR2 absence or antagonism prevents cystic fibrosis pulmonary manifestations. Journal of Cystic Fibrosis. https://doi.org/10.1016/j.jcf.2018.05.013

AGTR2 absence or antagonism prevents cystic fibrosis pulmonary manifestations. / Darrah, Rebecca J.; Jacono, Frank J.; Joshi, Neha; Mitchell, Anna L.; Sattar, Abdus; Campanaro, Cara K.; Litman, Paul; Frey, Jennifer; Nethery, David E.; Barbato, Eric S.; Hodges, Craig A.; Corvol, Harriet; Cutting, Garry R; Knowles, Michael R.; Strug, Lisa J.; Drumm, Mitchell L.

In: Journal of Cystic Fibrosis, 01.01.2018.

Research output: Contribution to journalArticle

Darrah, RJ, Jacono, FJ, Joshi, N, Mitchell, AL, Sattar, A, Campanaro, CK, Litman, P, Frey, J, Nethery, DE, Barbato, ES, Hodges, CA, Corvol, H, Cutting, GR, Knowles, MR, Strug, LJ & Drumm, ML 2018, 'AGTR2 absence or antagonism prevents cystic fibrosis pulmonary manifestations' Journal of Cystic Fibrosis. https://doi.org/10.1016/j.jcf.2018.05.013
Darrah, Rebecca J. ; Jacono, Frank J. ; Joshi, Neha ; Mitchell, Anna L. ; Sattar, Abdus ; Campanaro, Cara K. ; Litman, Paul ; Frey, Jennifer ; Nethery, David E. ; Barbato, Eric S. ; Hodges, Craig A. ; Corvol, Harriet ; Cutting, Garry R ; Knowles, Michael R. ; Strug, Lisa J. ; Drumm, Mitchell L. / AGTR2 absence or antagonism prevents cystic fibrosis pulmonary manifestations. In: Journal of Cystic Fibrosis. 2018.
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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.",
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AU - Darrah, Rebecca J.

AU - Jacono, Frank J.

AU - Joshi, Neha

AU - Mitchell, Anna L.

AU - Sattar, Abdus

AU - Campanaro, Cara K.

AU - Litman, Paul

AU - Frey, Jennifer

AU - Nethery, David E.

AU - Barbato, Eric S.

AU - Hodges, Craig A.

AU - Corvol, Harriet

AU - Cutting, Garry R

AU - Knowles, Michael R.

AU - Strug, Lisa J.

AU - Drumm, Mitchell L.

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N2 - 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.

AB - 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.

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