Physiological significance of two common haplotypes of human angiotensinogen using gene targeting in the mouse

Abstract

Angiotensinogen (AGT) was the first gene to be genetically linked to hypertension in humans. Analysis of the gene sequence identified a number of polymorphisms, several of which were reported associated with increased blood pressure (BP) or other cardiovascular diseases. One haplotype of the human AGT (hAGT) gene consisting of an allele at the -6 (A vs. G) position in the promoter and the sequence encoding amino acid 235 (Thr vs. Met) attracted the most attention and has been the subject of numerous association studies. In this report, we addressed the physiological relevance of alleles at these two positions using an experimental mouse model system. Transgenic mice were generated by targeting each haplotype [-6G/235Met (GM) and -6A/235Thr (AT)] as a single copy transgene to the mouse hypoxanthine phosphoribosyl transferase locus, allowing direct comparison of the two transgenes in vivo. Our results indicate that both transgenes exhibit the same transcriptional activity and produce similar levels of hAGT protein in the plasma of the transgenic mice. BP analysis was performed in double transgenic mice generated by breeding each hAGT line to mice expressing a human renin gene. A small but significant increase in BP and relative heart weight was demonstrated by mice carrying the GM haplotype. Moreover, compensatory downregulation of endogenous renin expression was more pronounced in mice containing the GM variant. Our findings suggest that the AT and GM haplotypes of the hAGT gene have no effect on gene expression, but may affect the cardiovascular system and the regulation of BP differently.

Differential Effects of Angiotensin II Type-1 Receptor Antisense Oligonucleotides on Renal Function in Spontaneously Hypertensive Rats

“…To determine the contribution of renal AT 1 Rs in the regulation of blood pressure, Crowley et al studied the effect of transplanting kidneys from AT 1A Ϫ/Ϫ mice into bilaterally nephrectomized wild-type nontransgenic mice, and vice versa. 13 These investigators estimated that basal blood pressure control resides in AT 1 Rs inside and outside the kidney.…”

“…G enetic manipulations that increase the activity of the renin-angiotensin system (RAS) systemically [1][2][3][4][5] or in specific organs (eg, brain and kidney) elevate blood pressure. 6,7 For example, overexpression of angiotensinogen and renin in renal proximal tubules 6 or in neurons and glia cells in brain 7 increased blood pressure without increasing circulating renin levels.…”

Role of Angiotensin Peptides Precursor in Ethanol Mediated Hepato toxicity: Perspective on Angiotensinogen

“…However, the transcriptional regulation by -6A nucleoside as compare to -6G is not known. Nevertheless, the transgenic studies demonstrate that this polymorphism neither changes the expression of the AGT nor increases blood pressure [55]. In conclusion, inhibition of the RAS in experimental animals and clinical studies has proven effective in counteracting fibrosis, cirrhosis, and hypertension [6,13,14,16].…”

Association between the angiotensinogen gene T174M polymorphism and hypertension risk in the Chinese population: a meta-analysis

“…Some previous studies revealed that the T174M variant was in tight linkage disequilibrium with other variants such as coding region variants, promoter variants and other yet unknown functional AGT polymorphisms. 5,[42][43][44] Therefore, it is necessary to evaluate the combined effect of T174M with other relevant polymorphisms in the AGT gene or different genes. The results from Yuan et al 13 suggested there was no evidence of association between T174M polymorphism by itself with hypertension in the Hani minority in China.…”