Angiotensinogen Genotype Affects Renal and Adrenal Responses to Angiotensin II in Essential Hypertension

Abstract

Background — Renovascular and adrenal responses to infused angiotensin II (Ang II) are intermediate phenotypes that may indirectly reflect tissue renin-angiotensin system activity. We examine herein angiotensinogen ( AGT ) as a candidate gene to help elucidate potential mechanisms for previously reported AGT linkage and association studies. Methods and Results — Renal plasma flow and plasma aldosterone were measured before and after a 45-minute infusion of Ang II (3 ng · kg −1 · min −1 ) in 190 hypertensive patients who were on carefully controlled high- and low-salt diets. Reduced renal vascular ( P =0.0002) and adrenal ( P =0.002) responses to infused exogenous Ang II were associated with the AGT −6A allele. In multiple logistic regression, greater body mass index, lower basal renal plasma flow, and higher diastolic blood pressure together with AGT −6A genotype were associated with lower renal vascular response. In contrast, only male sex and AGT −6A genotype were associated with lower adrenal response. When both the renal and adrenal responses to Ang II were in the lowest tertile, the AGT −6AA genotype was present in 55.6%; in contrast, when both responses were in the upper 2 tertiles, the −6AA genotype was present in only 17.8% ( P =0.001). Conclusions — A clear association between AGT genotype and response to infused Ang II was demonstrated for both the renal vasculature and the adrenal, consistent with the hypothesis that the AGT −6A genotype results in increased tissue expression of angiotensinogen and Ang II.

Genetics of hypertension

“…141,142 One group 143 reported more rapid progression to end-stage renal disease in diabetics with the 235T variant while another did not. 144 Consistent with the notion that the Ϫ6A (or 235T) allele of AGT results in increased tissue expression of angiotensinogen, we found that both normotensive homozygous carriers of the 235T AGT variant (most with a positive family history of hypertension) 145 and hypertensive patients with the Ϫ6AA genotype 146 showed significant blunting of renal vascular response to infused angiotensin II. This blunting (less than usual reduction of renal blood flow in response to infused angiotensin II on a high salt diet) is presumably the result of higher intrarenal angiotensin II production resulting in downregulation of vascular angiotensin II receptors.…”

“…There was also blunting of the normal stimulation of adrenal aldosterone production by infused angiotensin II on a low salt diet in hypertensive patients with the AGT Ϫ6AA genotype. 146 Interestingly, there was no association between AGT genotype and blood pressure response to salt change in our studies (comparing blood pressures at the end of one week on 200 mEq sodium per day and 1 week on 10 mEq/day) (unpublished observations, 2003). In one study of normotensive and hypertensive persons over age 60, the AGT 235T genotype was associated with a lesser diastolic response to changes in salt intake.…”

G-6A Polymorphism of the Angiotensinogen Gene and Its Association With Left Ventricular Mass in Asymptomatic Young Adults from a Biethnic CommunityThe Bogalusa Heart Study

“…29 It is of interest that a reduced renal vascular response to exogenous angiotensin II was found among hypertensive carriers of the A(-6) allele, which has been attributed to an effective feedback downregulation of angiotensin II type 1 receptors to any rise in AGT related to A(-6) allele. 30 Altogether, it appears that the genotypic effect of the A(-6) on LVM and LVMI through modulation of AGT levels may be marginal only. Speculatively, it is likely that the variant allele may be a genetic marker reflecting the complex interplay of the RAS genes and that the observed genotypic effect may be caused by linkage disequilibrium with another closely linked polymorphism within the AGT gene or nearby genes.…”

Genetic Risk of Atherosclerotic Renal Artery Disease

“…5 Finally, the angiotensinogen Met235Thr (AGT Met235Thr) polymorphism is of interest because the Thr allele of this polymorphism is associated with high plasma levels of AGT and increased responsiveness to angiotensin II. 6 In addition to studies of angiotensin II and its precursors, many studies have highlighted the importance of endothelium-derived nitric oxide (NO) in inhibiting atherosclerotic disease and the possibility that impairment of endothelial NO production promotes atherosclerosis. NO is produced by endothelial nitric oxide synthase (eNOS).…”