Differential effect of two haplotypes of the human angiotensinogen gene on blood pressure in transgenic mice

Abstract

Angiotensinogen (AGT) gene locus is associated with human essential hypertension and over‐expression of the AGT gene increases blood pressure in transgenic mice. Human AGT gene has A/G polymorphic sites at ‐6 and ‐217 positions in its promoter. The frequency of AA haplotype of the human AGT gene containing ‐6A:‐217A is significantly increased in African‐American hypertensive patients as compared to the AG haplotype‐6A:‐217G. Reporter constructs containing AA haplotype of the AGT gene promoter have increased promoter activity on transient transfection in human liver cells as compared to the AG haplotype. In order to understand the role of AA and AG haplotypes on hAGT expression in an in vivo situation, we have generated double transgenic mice containing either haplotype AA or AG of the hAGT gene (using knock‐in strategy at the HPRT locus) and human renin gene. Our studies show that transgenic mice containing AA haplotype have 1.6 fold increase in the AGT mRNA level in the liver as compared to the transgenic mice containing AG haplotype. In addition, Western blot and immunohistochemistry shows that liver and kidney of transgenic mice containing AA haplotype have increased hAGT protein level as compared to AG haplotype. In addition, blood pressure of three months old male transgenic mice containing AA haplotype is increased by about 8‐10 mmHg as compared to the transgenic mice containing AG haplotype. Supported by NHLBI.