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

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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.