AGTR2 absence or antagonism prevents cystic fibrosis pulmonary manifestations.

Autor: Darrah RJ; Frances Payne Bolton School of Nursing, Case Western Reserve University, Cleveland, OH 44106, USA; Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH 44106, USA. Electronic address: rjm11@case.edu., Jacono FJ; Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA; Department of Medicine, Louis Stokes Cleveland VA Medical Center, Cleveland, OH 44106, USA., Joshi N; Department of Pediatrics, Case Western Reserve University, Cleveland, OH 44106, USA., Mitchell AL; Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH 44106, USA., Sattar A; Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44106, USA., Campanaro CK; Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA., Litman P; Frances Payne Bolton School of Nursing, Case Western Reserve University, Cleveland, OH 44106, USA., Frey J; Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH 44106, USA., Nethery DE; Department of Medicine, Louis Stokes Cleveland VA Medical Center, Cleveland, OH 44106, USA., Barbato ES; Frances Payne Bolton School of Nursing, Case Western Reserve University, Cleveland, OH 44106, USA., Hodges CA; Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH 44106, USA; Department of Pediatrics, Case Western Reserve University, Cleveland, OH 44106, USA., Corvol H; Sorbonne Universités, UPMC Univ Paris 06, INSERM, Centre de Recherche Saint-Antoine (CRSA), Paris 75012, France; Pneumologie pédiatrique, APHP, Hôpital Trousseau, Paris 75012, France., Cutting GR; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA., Knowles MR; Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North, Carolina, 27599, USA., Strug LJ; Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 0A4; Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada M5T 3M7., Drumm ML; Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH 44106, USA; Department of Pediatrics, Case Western Reserve University, Cleveland, OH 44106, USA.
Jazyk: angličtina
Zdroj: Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society [J Cyst Fibros] 2019 Jan; Vol. 18 (1), pp. 127-134. Date of Electronic Publication: 2018 Jun 22.
DOI: 10.1016/j.jcf.2018.05.013
Abstrakt: 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.
(Copyright © 2018 The Author(s). Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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