Preventing a protein called AGTR2 from going about its work — either by removing it through genetic engineering or by using pharmacological agents to silence it — improved lung function in mouse models of cystic fibrosis (CF), a study reports.
Earlier work linking this protein to pulmonary disease in CF patients, including those of young age, was further supported by this study.
The research, “AGTR2 absence or antagonism prevents cystic fibrosis pulmonary manifestations,” was published in the Journal of Cystic Fibrosis.
Genetic differences unrelated to CFTR gene mutations — the cause of CF — are associated with lung disease in these patients. Specifically, a genome-wide association study (GWAS) in more 6,000 individuals spotted variants (differences) related to the severity of CF pulmonary disease that included the type 2 angiotensin II receptor (AGTR2) gene. [That study was published in 2015.]
The protein AGRT2 is a component of the renin-angiotensin system (RAS), a pathway of peptides mostly considered of importance for their role in regulating blood pressure and maintaining body fluid balance. Little is known about how RAS might contribute to pulmonary disease.
But the RAS pathway is known to be altered in CF patients, including its increased activation in response to salt deprivation. Higher serum levels of angiotensin converting enzyme, which mediates the generation of the biologically active angiotensin II, also correlate with a faster decline in lung function, suggesting that lower angiotensin signaling may be beneficial.
Led by researchers at Case Western Reserve University, the investigators wondered if manipulating the angiotensin pathway may work to treat CF patients.
First, they conducted a genetic analysis of samples from 126 CF patients — all treated as infants and children at a university-affiliated CF clinic. The patients’ mean age at enrollment of 9.3 years, younger than those involved with the GWAS study.
The results confirmed GWAS findings — that is, a specific variant of AGTR2 (known as rs5952223) was seen to be associated with worse pulmonary function, assessed by standard measures of lung health that include forced expiratory volume in one second, forced vital capacity, and forced expiratory flow.
“The replication of the association in younger individuals suggests the modifying effects may be occurring early in the disease process,” the scientists wrote.
Second, they used two CF mouse models to evaluate how a missing Agtr2 gene might impact lung function. They found that removing Agtr2 in the animals worked to normalize pulmonary function. Similar improvements were also seen using under-the-skin injections of a selective AGTR2 blocker known as PD123,319. The AGTR2 blocker was administered over 12 weeks, starting at weaning.
The research team emphasized that, while the mouse CF models of CF do not naturally progress to more severe disease stages and are not prone to infections similar to those found in CF patients, they are seen to be a good model of early CF lung disease, an important time window for treatment.
“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,” the researchers wrote.
Importantly, “the beneficial effects were not CF gene mutation dependent,” the team emphasized, suggesting that pharmaceutical compounds that target and block AGTR2 “may potentially benefit all CF patients, regardless of CFTR genotype.”
And, “as there are clinically approved drugs available to target the renin-angiotensin signaling system, these findings may be quickly translated to human clinical trials,” the researchers added.
Further work, however, is needed to determine the exact mechanism linking AGTR2 to CF lung disease.
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