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

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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.

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Acknowledgements

We thank the participants and their families, Alice Scott, RN, research study coordinator, and Patricia Brown, RN, research nurse, both of whom have no conflicts of interest. We also acknowledge the Biomarker Analytical Core of Wake Forest Baptist Health for their services in measuring uric acid and the RAS.

Funding

This study is funded by the National Heart, Lung, and Blood Institute (R01 HL146818), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (P01 HD047584; HD084227), the American Heart Association (14GRNT20480131; 18TPA34170522), the Clinical Research Unit of Wake Forest Baptist Medical Center (NIH/NCRR M01 RR07122), the Wake Forest Clinical and Translational Science Institute (NIH/NCATS UL1 TR001420), and Forsyth Medical Center and Wake Forest School of Medicine Department of Pediatrics research funds. The funding agencies had no role in the design of the study, collection and analysis of the data, or the decision to publish.

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Correspondence to Andrew M. South.

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Prior presentations: The current manuscript was presented in abstract form at Experimental Biology on April 24, 2018 and reports data from a subset of participants that are part of a larger, ongoing cohort study. Subsets of the study population were included in prior publications, including “Renal function and blood pressure are altered in adolescents born preterm,” Pediatr Nephrol. 2019;34:137–144 (PMCID PMC6237649); “Association between preterm birth and the renin−angiotensin system in adolescence: influence of sex and obesity,” J Hypertens. 2018;36:2092–2101 (PMCID PMC6148403); “Antenatal corticosteroids and the renin–angiotensin-aldosterone system in adolescents born preterm,” Pediatr Res. 2017;81:88–93 (PMCID PMC5646358); “Antenatal corticosteroids and cardiometabolic outcomes in adolescents born with very low birth weight,” Pediatr Res. 2017;82:697–703 (PMCID PMC5599338); “Adiposity in adolescent offspring born prematurely to mothers with preeclampsia,” J Pediatr. 2013;162:912–917 (PMCID PMC3785107); “The renin–angiotensin–aldosterone system in adolescent offspring born prematurely to mothers with preeclampsia,” J Renin-Angiotensin–Aldosterone Syst. 2015;16:529–538 (PMCID PMC4278943); “Antenatal steroid exposure and heart rate variability in adolescents born with very low birth weight,” Pediatr Res. 2017;81:57–62 (PMCID PMC5235986); “Preterm birth is associated with higher uric acid levels in adolescents,” J Pediatr. 2015;167:76–80 (PMCID PMC4485952); “Obesity is associated with higher blood pressure and higher levels of angiotensin II but lower angiotensin-(1–7) in adolescents born preterm,” J Pediatr. 2019;205:55–60.e51 (PMID 30404738); “Antenatal steroid exposure, aerobic fitness, and physical activity in adolescents born preterm with very low birth weight,” J Pediatr. 2019;215:98–106.e2 (PMCID: PMC6920012); and “Influence of race on the effect of premature birth on salivary cortisol response to stress in adolescents,” Pediatr Res. 2019. https://doi.org/10.1038/s41390-019-0682-3.

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South, A.M., Shaltout, H.A., Nixon, P.A. et al. Association of circulating uric acid and angiotensin-(1–7) in relation to higher blood pressure in adolescents and the influence of preterm birth. J Hum Hypertens 34, 818–825 (2020). https://doi.org/10.1038/s41371-020-0335-3

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