Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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

Journal of Human Hypertension volume 34, pages 818–825 (2020)Cite this article

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Code availability

The specific SAS code used in generating the results of this paper are available upon reasonable request.

References

  1. Benjamin EJ, Virani SS, Callaway CW, Chang AR, Cheng S, Chiuve SE, et al. Heart disease and stroke statistics—2018 update: a report from the American Heart Association. Circulation. 2018;137:e67–492.

    Google Scholar 

  2. Muntner P, Carey RM, Gidding S, Jones DW, Taler SJ, Wright JT, et al. Potential US population impact of the 2017 ACC/AHA High Blood Pressure Guideline. Circulation. 2018;137:109–18.

    Article  Google Scholar 

  3. Evensen KAI, Steinshamn S, Tjønna AE, Stølen T, Høydal MA, Wisløff U, et al. Effects of preterm birth and fetal growth retardation on cardiovascular risk factors in young adulthood. Early Hum Dev. 2009;85:239–45.

    Article  Google Scholar 

  4. Sundström J, Sullivan L, D’Agostino RB, Levy D, Kannel WB, Vasan RS. Relations of serum uric acid to longitudinal blood pressure tracking and hypertension incidence. Hypertension. 2005;45:28–33.

    Article  Google Scholar 

  5. Washburn LK, Nixon PA, Russell GB, Snively BM, O’Shea TM. Preterm birth is associated with higher uric acid levels in adolescents. J Pediatr. 2015;167:76–80.

    Article  Google Scholar 

  6. Yu M-A, Sánchez-Lozada LG, Johnson RJ, Kang D-H. Oxidative stress with an activation of the renin-angiotensin system in human vascular endothelial cells as a novel mechanism of uric acid-induced endothelial dysfunction. J Hypertens. 2010;28:1234–42.

    PubMed  Google Scholar 

  7. Shaltout HA, Figueroa JP, Rose JC, Diz DI, Chappell MC. Alterations in circulatory and renal angiotensin-converting enzyme and angiotensin-converting enzyme 2 in fetal programmed hypertension. Hypertension. 2009;53:404–8.

    Article  CAS  Google Scholar 

  8. Sampaio WO, Henrique de Castro C, Santos RAS, Schiffrin EL, Touyz RM. Angiotensin-(1-7) counterregulates angiotensin II signaling in human endothelial cells. Hypertension. 2007;50:1093–8.

    Article  CAS  Google Scholar 

  9. Washburn LK, Brosnihan KB, Chappell MC, Diz DI, Gwathmey TM, Nixon PA, et al. The renin–angiotensin–aldosterone system in adolescent offspring born prematurely to mothers with preeclampsia. J Renin Angiotensin Aldosterone Syst. 2015;16:529–38.

    Article  CAS  Google Scholar 

  10. South AM, Nixon PA, Chappell MC, Diz DI, Russell GB, Jensen ET, et al. Association between preterm birth and the renin−angiotensin system in adolescence: influence of sex and obesity. J Hypertens. 2018;36:2092–101.

    Article  CAS  Google Scholar 

  11. Mulè G, Castiglia A, Morreale M, Geraci G, Cusumano C, Guarino L, et al. Serum uric acid is not independently associated with plasma renin activity and plasma aldosterone in hypertensive adults. Nutr Metab Cardiovasc Dis. 2017;27:350–9.

    Article  Google Scholar 

  12. Russell BK. Babies who are small for gestational age. Pediatr Rev. 1995;16:354.

    Article  Google Scholar 

  13. Barlow SE. Expert committee recommendations regarding the prevention, assessment, and treatment of child and adolescent overweight and obesity: summary report. Pediatrics. 2007;120 Suppl 4:S164–92.

    Article  Google Scholar 

  14. Taylor SJ, Whincup PH, Hindmarsh PC, Lampe F, Odoki K, Cook DG. Performance of a new pubertal self-assessment questionnaire: a preliminary study. Paediatr Perinat Epidemiol. 2001;15:88–94.

    Article  CAS  Google Scholar 

  15. U.S. Department of Health and Human Services and U.S. Department of Agriculture. 2015-2020 Dietary Guidelines for Americans. U.S. Department of Health and Human Services and U.S. Department of Agriculture; 2015. http://health.gov/dietaryguidelines/2015/guidelines/.

  16. Update on the 1987 Task Force Report on High Blood Pressure in Children and Adolescents: a Working Group Report from the National High Blood Pressure Education Program. National High Blood Pressure Education Program Working Group on Hypertension Control in Children and Adolescents. Pediatrics. 1996;98:649–58.

  17. Rosner B, Cook N, Portman R, Daniels S, Falkner B. Determination of blood pressure percentiles in normal-weight children: some methodological issues. Am J Epidemiol. 2008;167:653–66.

    Article  CAS  Google Scholar 

  18. South AM, Nixon PA, Chappell MC, Diz DI, Russell GB, Jensen ET, et al. Renal function and blood pressure are altered in adolescents born preterm. Pediatr Nephrol. 2019;34:137–44.

    Article  Google Scholar 

  19. Flynn JT, Kaelber DC, Baker-Smith CM, Blowey D, Carroll AE, Daniels SR, et al. Clinical practice guideline for screening and management of high blood pressure in children and adolescents. Pediatrics. 2017;140:e20171904.

    Article  Google Scholar 

  20. Chappell MC. Biochemical evaluation of the renin-angiotensin system: the good, bad, and absolute? Am J Physiol Heart Circ Physiol. 2016;310: H137–52.

  21. Croghan C, Egeghy PP. Methods of dealing with values below the limit of detection using SAS. St. Petersburg, FL: Southeastern SAS User Group; 2003.

    Google Scholar 

  22. Shrier I, Platt RW. Reducing bias through directed acyclic graphs. BMC Med Res Methodol. 2008;8:70.

    Article  Google Scholar 

  23. Cappuccio FP, Strazzullo P, Farinaro E, Trevisan M. Uric acid metabolism and tubular sodium handling: results from a population-based study. J Am Med Assoc. 1993;270:354–9.

    Article  CAS  Google Scholar 

  24. Viazzi F, Antolini L, Giussani M, Brambilla P, Galbiati S, Mastriani S, et al. Serum uric acid and blood pressure in children at cardiovascular risk. Pediatrics. 2013;132:e93–e9.

    Article  Google Scholar 

  25. Perez-Ruiz F, Calabozo M, Erauskin GG, Ruibal A, Herrero-Beites AM. Renal underexcretion of uric acid is present in patients with apparent high urinary uric acid output. Arthritis Care Res. 2002;47:610–3.

    Article  CAS  Google Scholar 

  26. Corry DB, Eslami P, Yamamoto K, Nyby MD, Makino H, Tuck ML. Uric acid stimulates vascular smooth muscle cell proliferation and oxidative stress via the vascular renin–angiotensin system. J Hypertens. 2008;26:269–75.

    Article  CAS  Google Scholar 

  27. Chappell M, Marshall A, Al Zayadneh EM, Shaltout H, Diz D. Update on the angiotensin converting enzyme 2-angiotensin (1–7)-Mas receptor axis: fetal programing, sex differences, and intracellular pathways. Front Endocrinol. 2014;4:201.

    Article  Google Scholar 

  28. Fabbrini E, Serafini M, Colic Baric I, Hazen SL, Klein S. Effect of plasma uric acid on antioxidant capacity, oxidative stress, and insulin sensitivity in obese subjects. Diabetes. 2014;63:976–81.

    Article  CAS  Google Scholar 

  29. South AM, Shaltout HA, Washburn LK, Hendricks AS, Diz DI, Chappell MC. Fetal programming and the angiotensin-(1-7) axis: a review of the experimental and clinical data. Clin Sci. 2019;133:55–74.

    Article  CAS  Google Scholar 

  30. Washburn LK, Nixon PA, Shaltout HA, South AM, O’Shea TM. Impaired stress-induced pressure natriuresis in young adults born with very low birth weight. Pediatr Acad Soc. 2017;E-PAS2017:(abstract 2300.1).

  31. Wang Y, Hu J-W, Lv Y-B, Chu C, Wang K-K, Zheng W-L, et al. The role of uric acid in hypertension of adolescents, prehypertension and salt sensitivity of blood pressure. Med Sci Monit. 2017;23:790–5.

    Article  CAS  Google Scholar 

  32. Ruys CA, Rotteveel J, van de Lagemaat M, Lafeber HN, Finken MJJ. Salt sensitivity of blood pressure at age 8 years in children born preterm. J Hum Hypertens. 2018;32:367–76.

    Article  Google Scholar 

  33. Wang Y, Chu C, Wang K-K, Hu J-W, Yan Y, Lv Y-B, et al. Effect of salt intake on plasma and urinary uric acid levels in chinese adults: an interventional trial. Sci Rep. 2018;8:1434.

    Article  Google Scholar 

  34. Grayson PC, Kim SY, LaValley M, Choi HK. Hyperuricemia and incident hypertension: a systematic review and meta-analysis. Arthritis Care Res. 2010;63:102–10.

    Article  Google Scholar 

  35. McMullan CJ, Borgi L, Fisher N, Curhan G, Forman J. Effect of uric acid lowering on renin-angiotensin-system activation and ambulatory BP: a randomized controlled trial. Clin J Am Soc Nephrol. 2017;12:807–16.

    Article  Google Scholar 

  36. Feig DI, Soletsky B, Johnson RJ. Effect of allopurinol on blood pressure of adolescents with newly diagnosed essential hypertension: a randomized trial. J Am Med Assoc. 2008;300:924–32.

    Article  CAS  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  1. Department of Pediatrics, Wake Forest School of Medicine and Brenner Children’s Hospital, Winston Salem, NC, USA

    Andrew M. South, Patricia A. Nixon & Lisa K. Washburn

  2. Cardiovascular Sciences Center, Wake Forest School of Medicine, Winston Salem, NC, USA

    Andrew M. South, Hossam A. Shaltout, Debra I. Diz, Mark C. Chappell & Lisa K. Washburn

  3. Department of Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest School of Medicine, Winston Salem, NC, USA

    Andrew M. South & Elizabeth T. Jensen

  4. Department of Surgery-Hypertension and Vascular Research, Wake Forest School of Medicine, Winston Salem, NC, USA

    Andrew M. South, Debra I. Diz & Mark C. Chappell

  5. Department of Obstetrics and Gynecology, Wake Forest School of Medicine, Winston Salem, NC, USA

    Hossam A. Shaltout

  6. Department of Pharmacology and Toxicology, School of Pharmacy, University of Alexandria, Alexandria, Egypt

    Hossam A. Shaltout

  7. Department of Health and Exercise Science, Wake Forest University, Winston Salem, NC, USA

    Patricia A. Nixon

  8. Department of Pediatrics, University of North Carolina School of Medicine, Chapel Hill, NC, USA

    T. Michael O’Shea

Authors
  1. Andrew M. South
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hossam A. Shaltout
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Patricia A. Nixon
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Debra I. Diz
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Elizabeth T. Jensen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. T. Michael O’Shea
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mark C. Chappell
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Lisa K. Washburn
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Andrew M. South.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41371-020-0335-3

This article is cited by

Search

Advanced search

Quick links