Differential Regulation of Blood Pressure in Transgenic Mice Containing ‐217A/G Polymorphism of Human Angiotensinogen Gene in Response to Immobilization Stress

Abstract

Stress is a risk factor for hypertension. However, the mechanism by which stress leads to hypertension is unclear. Stress induces glucocorticoid secretion. Increased glucocorticoids trigger DNA binding activity of C/EBPβ and C/EBPδ via glucocorticoid receptors (GR). Here we show that expression of C/EBPβ, C/EBPδ and AGT genes are significantly increased in adrenal medulla, liver and kidney of rats subjected to Immobilization stress (IS).Renin‐angiotensin system (RAS) plays an important role in regulating blood pressure. Transcription factors C/EBPβ and C/EBPδ are important in regulation of human angiotensinogen (hAGT) gene. We have shown that hAGT gene contains an A/G polymorphism at ‐217, and frequency of ‐217A allele is increased in African‐American hypertensive subjects. Nucleotide sequence of hAGT gene promoter containing ‐217A has homology with the consensus CCAAT/enhancer binding protein (C/EBP) and GR binding site. Therefore, we have generated transgenic mice containing either ‐217A or ‐217G haplotype of the hAGT gene. These transgenic mice were subjected to IS. We found that mice containing haplotype ‐217A subjected to IS has 1.72 fold increased expression of hAGT in liver and 8mmHg increase in blood pressure. Whereas the mice containing haplotype ‐217G shows only 1.2 fold increase in hAGT expression and no significant change in blood pressure. These results suggest that stress leads to the differential regulation of human AGT gene.