Hypertension Research (2020) 43:832–834

https://doi.org/10.1038/s41440-020-0481-6

COMMENT

Uric acid and hypertension

Miguel A. Lanaspa1 Ana Andres-Hernando1 Masanari Kuwabara1,2
● ●

Key words Uric acid Hypertension Risk factor Causality Mechanism

● ● ● ●

Received: 22 November 2019 / Revised: 28 November 2019 / Accepted: 28 November 2019 / Published online: 8 June 2020
© The Japanese Society of Hypertension 2020

The association between serum uric acid levels and high showed a negative relationship between hyperuricemia and
blood pressure in humans is well established. For example, hypertension [8]. However, it is important to note that
a cross-sectional study determined that each 1 mg/dL Mendelian studies involve gene-dependent associations,
increase in serum uric acid contributes a 20% increased and even though hyperuricemia has an important genetic
prevalence of hypertension in a general population not component, it is primarily caused by life habits and diet.
1234567890();,:
1234567890();,:

treated with hyperuricemia and hypertension [1]. Similarly, Nevertheless, the current evidence suggests the need for
in longitudinal cohort studies, asymptomatic hyperuricemia further studies about the relationship between serum uric
without comorbidities predicts the development of hyper- acid and hypertension, and specifically studies focusing on
tension [2]. Moreover, hyperuricemia also contributes to the life habits, including drinking alcohol, such as the Saku
development of hypertension from prehypertension [3]. study recently published in this journal.
Based on these observations, the lowering of serum uric The Saku study was conducted retrospectively using the
acid levels has become an intriguing therapeutic approach in cohort data (a mean of 4.0 years follow-up) to evaluate
hypertension. In this regard, several randomized placebo the risk factors for high uric acid with hypertension [9].
control trials (RCTs) have shown that the reduction of uric The study group enrolled 7848 participants who had
acid, either with a xanthine oxidase inhibitor (allopurinol) undergone a medical checkup. After adjustment for alcohol
or with a uricosuric agent (probenecid), substantially consumption, hyperuricemia was found to be independently
decreased blood pressure in adolescents [4, 5]. Similarly, a associated with the development of hypertension, with
recent RCT also showed that pegloticase, a recombinant hazard ratios (HRs) of 1.37 in men and 1.54 in women.
uricase conjugated to polyethylene glycol, significantly Furthermore, among nonalcohol drinkers, hyperuricemia
decreased blood pressure compared with placebo in subjects was also independently associated with the development of
with chronic refractory gout [6]. From these studies, a direct hypertension, with HRs of 1.29 in men and 1.57 in women.
causal relationship between serum uric acid and blood Importantly, the interaction between hyperuricemia or
pressure could be extrapolated. However, not all RCTs alcohol consumption and sex was not significant. Based on
conducted have been able to elucidate such a clear causal these observations, the authors concluded that hyperur-
role for uric acid in hypertension. For example, in the icemia could predict the development of hypertension
FEATHER study, febuxostat did not significantly decrease independently of alcohol intake. Thus, the novelty of this
blood pressure compared with placebo in subjects with study relates to the finding that serum uric acid is still
asymptomatic hyperuricemia and stage 3 chronic kidney associated with the development of hypertension even after
diseases [7]. Moreover, most Mendelian randomized studies excluding the effects of alcohol consumption on serum uric
acid [10], which is a well-known risk factor for hyperur-
icemia. In addition, the strength of the study relies on its
analysis with well-adjusted cofactors, including age, esti-
* Masanari Kuwabara mated glomerular filtration rate, diabetes, dyslipidemia,
[email protected]
body mass index, smoking status, physical activity, family
1
Division of Renal Diseases and Hypertension, School of Medicine, history, and systolic blood pressure. However, the limitation
University of Colorado Denver, Denver, CO, USA of the study is the lack of detailed medication data. It is
2
Intensive Care Unit and Department of Cardiology, Toranomon known that some antihypertensive agents, such as thiazide,
Hospital, Tokyo, Japan increase serum uric acid levels, while other medications,
Uric acid and hypertension 833

Fig. 1 The mechanisms by

which hyperuricemia causes
hypertension; crystal
(extracellular uric acid) pathway
and crystal-independent
(intracellular uric acid) pathway.

including losartan, fenofibrate, and sodium–glucose the elevation of aldose reductase expression results in the
cotransporter-2 (SGLT2) inhibitors, decrease serum uric activation of the polyol pathway, leading to two main
acid levels. The use of these medications in the population consequences: the blockade of nitric oxide production and
analyzed should have been taken into consideration. the production of endogenous fructose. Both of these
Moreover, observational studies such as the Saku study, mechanisms seem to play an important deleterious role in
although clinically relevant, are not designed to address the pathogenesis of high blood pressure in the endothe-
whether there is causality between serum uric acid and lium as the blockade of aldose reductase or fructokinase,
hypertension. Therefore, there is still the need to identify the the enzyme involved in the metabolism of fructose,
potential molecular and cellular mechanisms whereby markedly improves endothelial cell function [15, 16]. The
hyperuricemia causes hypertension in basic and clinical molecular mechanism whereby uric acid upregulates
studies. aldose reductase and causes endothelial cell dysfunction
Classically, the proposed mechanism whereby uric acid seems to be mediated by its prooxidant properties. More
can cause hypertension relates to its primary deleterious specifically, it has been shown that uric acid induces
effects on the kidney. These mechanisms include the mitochondrial dysfunction and superoxide generation
activation of the intrarenal renin–angiotensin system and through the activation of nicotinamide adenine dinucleo-
the deposition of urate crystals in the urinary lumen. tide phosphate (NADPH) oxidases, thus depleting energy
However, recent evidence indicates that uric acid can (adenosine triphosphate (ATP)) capacity [17]. Of interest,
cause direct endothelial injury and dysfunction. In this mitochondrial ATP production is important for proper
regard, Klauser et al. demonstrated the presence of urate endothelial signaling and function. In summary, these
deposits in the aorta and coronary arteries of patients with studies highlight new evidence of the direct deleterious
gout by dual-energy computer tomography and their effects of uric acid on the endothelium, which may be
association with higher coronary calcium score [11]. The important underlying factors in the pathogenesis of
deposition of urate crystals in main vessels may trigger a hypertension (Fig. 1) [18, 19].
similar proinflammatory response as it is observed in the
kidney, thus causing more direct endothelial damage [12]. Compliance with ethical standards
A crystal-independent mechanism has also been postu-
lated. It is well known that uric acid impairs endothelial Conflict of interest MK reports receiving a research grant from Tor-
anomon Hospital, Okinaka Memorial Institute for Medical Research,
function by reducing endothelial nitric oxide synthase and the Gout Research Foundation in Japan. The remaining authors
phosphorylation under hypoxic conditions [13]. More- have nothing to disclose.
over, recently, several groups have found that soluble uric
acid upregulates the expression of aldose reductase in Publisher’s note Springer Nature remains neutral with regard to
the endothelium and other tissues [14, 15]. Interestingly, jurisdictional claims in published maps and institutional affiliations.
834 M. A. Lanaspa et al.

References 11. Klauser AS, Halpern EJ, Strobl S, Gruber J, Feuchtner G,

Bellmann-Weiler R, et al. Dual-energy computed tomography
1. Kuwabara M, Niwa K, Nishi Y, Mizuno A, Asano T, Masuda K, detection of cardiovascular monosodium urate deposits in patients
et al. Relationship between serum uric acid levels and hyperten- with gout. JAMA Cardiol. 2019. https://doi.org/10.1001/jamaca
sion among Japanese individuals not treated for hyperuricemia rdio.2019.3201.
and hypertension. Hypertens Res. 2014;37:785–9. 12. Kuwabara M, Kanbay M, Hisatome I. Uric acid and hypertension
2. Kuwabara M, Niwa K, Hisatome I, Nakagawa T, Roncal-Jimenez because of arterial stiffness. Hypertension. 2018;72:582–4.
CA, Andres-Hernando A, et al. Asymptomatic hyperuricemia 13. Otani N, Toyoda S, Sakuma M, Hayashi K, Ouchi M, Fujita T,
without comorbidities predicts cardiometabolic diseases: five-year et al. Effects of uric acid on vascular endothelial function from
Japanese cohort study. Hypertension. 2017;69:1036–44. bedside to bench. Hypertens Res. 2018;41:923–31.
3. Kuwabara M, Hisatome I, Niwa K, Hara S, Roncal-Jimenez CA, 14. Sanchez-Lozada LG, Andres-Hernando A, Garcia-Arroyo FE,
Bjornstad P, et al. Uric acid is a strong risk marker for developing Cicerchi C, Li N, Kuwabara M, et al. Uric acid activates aldose
hypertension from prehypertension: a 5-year Japanese cohort reductase and the polyol pathway for endogenous fructose and fat
study. Hypertension. 2018;71:78–86. production causing development of fatty liver in rats. J Biol
4. Soletsky B, Feig DI. Uric acid reduction rectifies prehypertension Chem. 2019;294:4272–81.
in obese adolescents. Hypertension. 2012;60:1148–56. 15. Huang Z, Hong Q, Zhang X, Xiao W, Wang L, Cui S, et al.
5. Feig DI, Soletsky B, Johnson RJ. Effect of allopurinol on blood Aldose reductase mediates endothelial cell dysfunction induced by
pressure of adolescents with newly diagnosed essential hyper- high uric acid concentrations. Cell Commun Signal. 2017;15:3.
tension: a randomized trial. JAMA. 2008;300:924–32. 16. Lanaspa MA, Kuwabara M, Andres-Hernando A, Li N,
6. Johnson RJ, Choi HK, Yeo AE, Lipsky PE. Pegloticase treatment Cicerchi C, Jensen T, et al. High salt intake causes leptin resis-
significantly decreases blood pressure in patients with chronic tance and obesity in mice by stimulating endogenous fructose
gout. Hypertension. 2019;74:95–101. production and metabolism. Proc Natl Acad Sci USA.
7. Kimura K, Hosoya T, Uchida S, Inaba M, Makino H, Maruyama 2018;115:3138–43.
S, et al. Febuxostat therapy for patients with Stage 3 CKD and 17. Lanaspa MA, Sanchez-Lozada LG, Choi YJ, Cicerchi C, Kanbay
asymptomatic hyperuricemia: a randomized trial. Am J Kidney M, Roncal-Jimenez CA, et al. Uric acid induces hepatic steatosis
Dis. 2018;72:798–810. by generation of mitochondrial oxidative stress: potential role in
8. Sedaghat S, Pazoki R, Uitterlinden AG, Hofman A, Stricker BH, fructose-dependent and -independent fatty liver. J Biol Chem.
Ikram MA, et al. Association of uric acid genetic risk score with 2012;287:40732–44.
blood pressure: the Rotterdam study. Hypertension. 18. Sanchez-Lozada LG, Lanaspa MA, Cristobal-Garcia M, Garcia-
2014;64:1061–6. Arroyo F, Soto V, Cruz-Robles D, et al. Uric acid-induced
9. Tatsumi Y, Asayama K, Morimoto A, Satoh M, Sonoda N, endothelial dysfunction is associated with mitochondrial altera-
Miyamatsu N, et al. Hyperuricemia predicts the risk for tions and decreased intracellular ATP concentrations. Nephron
developing hypertension independent of alcohol drinking status Exp Nephrol. 2012;121:e71–78.
in men and women: the Saku study. Hypertens Res. 2020; 19. Wilson C, Lee MD, Heathcote HR, Zhang X, Buckley C, Girkin
43:442–49. JM, et al. Mitochondrial ATP production provides long-range
10. Kuwabara M. Hyperuricemia, cardiovascular disease, and hyper- control of endothelial inositol trisphosphate-evoked calcium sig-
tension. Pulse. 2016;3:242–52. naling. J Biol Chem. 2019;294:737–758.