Association of circulating uric acid and angiotensin-(1-7) in relation to higher blood pressure in adolescents and the influence of preterm birth

Abstract

Elevated serum uric acid increases the risk of hypertension, and individuals born preterm have higher blood pressure (BP) and uric acid, but the mechanisms remain unclear. Preclinical studies demonstrate uric acid increases BP via increased renin-angiotensin system (RAS) expression, especially angiotensin (Ang) II, but the association of uric acid with Ang-(1-7) is unknown. Ang-(1-7), an alternative RAS product, counteracts Ang II by stimulating sodium excretion, vasodilation, and nitric oxide, thus contributing to lower BP. Plasma Ang-(1-7) is lower in preterm-born adolescents. We hypothesized uric acid is associated with a higher ratio of Ang II to Ang-(1-7) in plasma, especially in preterm-born adolescents. We measured BP, serum uric acid, and plasma RAS components in a cross-sectional analysis of 163 14-year olds (120 preterm, 43 term). We estimated the associations between uric acid and the RAS using generalized linear models adjusted for sex, obesity, sodium intake, and fat intake, stratified by birth status. Uric acid was positively associated with Ang II/Ang-(1-7) (adjusted β (aβ): 0.88 mg/dl, 95% CI 0.17-1.58), plasma renin activity (aβ: 0.32 mg/dl, 95% CI 0.07-0.56), and aldosterone (aβ: 1.26 mg/dl, 95% CI 0.18-2.35), and inversely with Ang-(1-7) (aβ: -1.11 mg/dl, 95% CI -2.39 to 0.18); preterm birth did not modify these associations. Higher Ang II/Ang-(1-7) was associated with higher uric acid in adolescents. As preterm birth is associated with higher BP and uric acid, but lower Ang-(1-7), the imbalance between uric acid and Ang-(1-7) may be an important mechanism for the development of hypertension.

Conflict of interest statement

Conflicts of interest: None.

Figures

Fig. 1

Study flow diagram

Fig. 2

A-BCorrelation between serum uric acid and plasma Ang II/Ang-(1–7) in preterm-born and term-born adolescents Loess fitted curves in black with confidence limits for mean predicted values in grey shading; individual data points and unadjusted generalized linear model regression coefficients with corresponding p values are provided. A: Preterm-birth cohort, unadjusted β (95% CI) 0.78 (−0.01, 1.56), p = 0.05. B: Term-birth cohort, unadjusted β (95% CI) 0.19 (−0.52, 0.9), p = 0.6. Ang, angiotensin.

Fig. 3

Conceptual diagram of the uric acid – Ang-(1–7) – BP association Programming events such as preterm birth may increase uric acid expression which then may suppress Ang-(1–7) expression but correspondingly increase Ang II expression. This in turn could lead to renal sodium retention and increased BP. In addition, Ang II-mediated increased oxidative stress, in part via upregulation of NF-κB and ERK and downregulation of PI3K leading to reduced eNOS but increased ROS, could increase inflammation in the kidneys, vasculature, and heart ultimately promoting development of hypertension and cardiovascular disease. Ang, angiotensin; BP, blood pressure; eNOS, endothelial nitric oxide synthase; ERK, extracellular regulated kinase; NF-κB, nuclear factor kappa enhancer of B cells; PI3K, phosphoinositide 3-kinase; RAS, renin-angiotensin system; ROS, reactive oxygen species.