An established body of literature supports the hypothesis that activation of a local tissue angiotensin (ANG) system in the extravascular tissue compartment of the lungs is required for lung fibrogenesis. Transcriptional activation of the angiotensinogen (AGT) gene is believed to be a critical and necessary step in this activation. This paper summarizes the data in support of this theory and discusses transcriptional regulation of AGT, with an emphasis on lung AGT synthesis as a determinant of fibrosis severity. Genetic data linking AGT polymorphisms to the severity of disease in Idiopathic Pulmonary Fibrosis are also discussed.

Purpose Single nucleotide polymorphisms in angiotensinogen at positions -20 and -6 are associated with increased severity and progression of various fibrotic diseases. Our earlier work demonstrated that the progression of Idiopathic Pulmonary Fibrosis was associated with the A-6 allele. This study examined the hypothesis that the homozygous CC genotype at -20 and the AA genotype at -6 would confer worse measures of pulmonary function (measured by pulmonary function tests) in Idiopathic Pulmonary Fibrosis. Method Multiple logistic regression analysis was applied to a NIH Lung Tissue Research Consortium cohort and Spanish cohort, while also adjusting for covariates to determine the effects of these SNPs on measures of pulmonary function. Results Analysis demonstrated that the CC genotype at -20 was strongly associated with reduced diffusing capacity in males in both cohorts (p = 0.0028 for LTRC and p = 0.017). In females, the AA genotype was significantly associated with lower FVC (p = 0.0082) and Valv (p = 0.022). In males, the haplotype CA at -20 and -6 in AGT was also strongly associated with reduced diffusing capacity in both cohorts. Conclusions This study is the first to demonstrate an association of angiotensinogen polymorphisms (-20A>C and -6G>A) with lower measures of pulmonary function in Idiopathic Pulmonary Fibrosis. It is also the first to relate the effect of gender in lung fibrosis with polymorphisms in angiotensinogen.