This review summarizes relevant studies concerning uric acid and possible links to hypertension, renal disease, and cardiovascular disease. Whether uric acid is an independent risk factor for such diseases is still a point of debate. Current evidence is presented.

Uric acid and cardiovascular risk.

Hyperuricemia is associated with hypertension, vascular disease, renal disease, and cardiovascular events. In this report, we review the epidemiologic evidence and potential mechanisms for this association. We also summarize experimental studies that demonstrate that uric acid is not inert but may have both beneficial functions (acting as an antioxidant) as well as detrimental actions (to stimulate vascular smooth muscle cell proliferation and induce endothelial dysfunction). A recently developed experimental model of mild hyperuricemia also provides the first provocative evidence that uric acid may have a pathogenic role in the development of hypertension, vascular disease, and renal disease. Thus, it is time to reevaluate the role of uric acid as a risk factor for cardiovascular disease and hypertension and to design human studies to address this controversy.

Is There a Pathogenetic Role for Uric Acid in Hypertension and Cardiovascular and Renal Disease

Recent experimental and human studies have shown that hyperuricemia is associated with hypertension, systemic inflammation, and cardiovascular disease mediated by endothelial dysfunction and pathologic vascular remodeling Elevated levels of C-reactive protein (CRP) have emerged as one of the most powerful independent predictors of cardiovascular disease In addition to being a marker of inflammation, recent evidence suggests that CRP may participate directly in the development of atherosclerotic vascular disease For investigating whether uric acid (UA)-induced inflammatory reaction and vascular remodeling is related to CRP, the UA-induced expression of CRP in human vascular smooth muscle cells (HVSMC) and human umbilical vein endothelial cells (HUVEC) was examined, as well as the pathogenetic role of CRP in vascular remodeling It is interesting that HVSMC and HUVEC expressed CRP mRNA and protein constitutively, revealing that vascular cells are another source of CRP production UA (6 to 12 mg/dl) upregulated CRP mRNA expression in HVSMC and HUVEC with a concomitant increase in CRP release into cell culture media Inhibition of p38 or extracellular signal-regulated kinase 44/42 significantly suppressed UA-induced CRP expression, implicating these pathways in the response to UA UA stimulated HVSMC proliferation whereas UA inhibited serum-induced proliferation of HUVEC assessed by 3H-thymidine uptake and cell counting, which was attenuated by co-incubation with probenecid, the organic anion transport inhibitor, suggesting that entry of UA into cells is responsible for CRP expression UA also increased HVSMC migration and inhibited HUVEC migration In HUVEC, UA reduced nitric oxide (NO) release Treatment of vascular cells with anti-CRP antibody revealed a reversal of the effect of UA on cell proliferation and migration in HVSMC and NO release in HUVEC, which suggests that CRP expression may be responsible for UA-induced vascular remodeling This is the first study to show that soluble UA, at physiologic concentrations, has profound effects on human vascular cells The observation that UA alters the proliferation/migration and NO release of human vascular cells, mediated by the expression of CRP, calls for careful reconsideration of the role of UA in hypertension and vascular disease

/pdf/uric-acid-induced-c-reactive-protein-expression-implication-6mqtoekln6.pdf

Uric Acid–Induced C-Reactive Protein Expression: Implication on Cell Proliferation and Nitric Oxide Production of Human Vascular Cells

Context Hyperuricemia is a predictor for the development of hypertension and is commonly present in new-onset essential hypertension. Experimentally increasing uric acid levels using a uricase inhibitor causes systemic hypertension in animal models. Objective To determine whether lowering uric acid lowers blood pressure (BP) in hyperuricemic adolescents with newly diagnosed hypertension. Design, Setting, and Patients Randomized, double-blind, placebo-controlled, crossover trial (September 2004-March 2007) involving 30 adolescents (aged 11-17 years) who had newly diagnosed, never-treated stage 1 essential hypertension and serum uric acid levels ≥6 mg/dL. Participants were treated at the Pediatric Hypertension Clinic at Texas Children's Hospital in Houston. Patients were excluded if they had stage 2 hypertension or known renal, cardiovascular, gastrointestinal tract, hepatic, or endocrine disease. Intervention Allopurinol, 200 mg twice daily for 4 weeks, and placebo, twice daily for 4 weeks, with a 2-week washout period between treatments. The order of the treatments was randomized. Main Outcome Measures Change in casual and ambulatory blood pressure. Results For casual BP, the mean change in systolic BP for allopurinol was −6.9 mm Hg (95% confidence interval [CI], −4.5 to −9.3 mm Hg) vs −2.0 mm Hg (95% CI, 0.3 to −4.3 mm Hg; P = .009) for placebo, and the mean change in diastolic BP for allopurinol was −5.1 mm Hg (95% CI, −2.5 to −7.8 mm Hg) vs −2.4 (95% CI, 0.2 to −4.1; P = .05) for placebo. Mean change in mean 24-hour ambulatory systolic BP for allopurinol was −6.3 mm Hg (95% CI, −3.8 to −8.9 mm Hg) vs 0.8 mm Hg (95% CI, 3.4 to −2.9 mm Hg; P = .001) for placebo and mean 24-hour ambulatory diastolic BP for allopurinol was −4.6 mm Hg (−2.4 to −6.8 mm Hg) vs −0.3 mm Hg (95% CI, 2.3 to −2.1 mm Hg; P = .004) for placebo. Twenty of the 30 participants achieved normal BP by casual and ambulatory criteria while taking allopurinol vs 1 participant while taking placebo (P  Conclusions In this short-term, crossover study of adolescents with newly diagnosed hypertension, treatment with allopurinol resulted in reduction of BP. The results represent a new potential therapeutic approach, although not a fully developed therapeutic strategy due to potential adverse effects. These preliminary findings require confirmation in larger clinical trials. Trial Registration clinicaltrials.gov Identifier: NCT00288184

https://jamanetwork.com/journals/jama/articlepdf/182461/jpc80008_924_932.pdf

Effect of Allopurinol on Blood Pressure of Adolescents With Newly Diagnosed Essential Hypertension: A Randomized Trial

https://www.ajkd.org/article/S0272-6386(05)01518-0/pdf

Use of Allopurinol in Slowing the Progression of Renal Disease Through Its Ability to Lower Serum Uric Acid Level

Previous studies have reported that uric acid stimulates vascular smooth muscle cell (VSMC) proliferation in vitro. We hypothesized that uric acid may also have direct proinflammatory effects on VSMCs. Crystal- and endotoxin-free uric acid was found to increase VSMC monocyte chemoattractant protein-1 (MCP-1) expression in a time- and dose-dependent manner, peaking at 24 hours. Increased mRNA and protein expression occurred as early as 3 hours after uric acid incubation and was partially dependent on posttranscriptional modification of MCP-1 mRNA. In addition, uric acid activated the transcription factors nuclear factor-κB and activator protein-1, as well as the MAPK signaling molecules ERK p44/42 and p38, and increased cyclooxygenase-2 (COX-2) mRNA expression. Inhibition of p38 (with SB 203580), ERK 44/42 (with UO126 or PD 98059), or COX-2 (with NS398) each significantly suppressed uric acid–induced MCP-1 expression at 24 hours, implicating these pathways in the response to uric acid. The ability of both n-acetyl-cysteine and diphenyleneionium (antioxidants) to inhibit uric acid–induced MCP-1 production suggested involvement of intracellular redox pathways. Uric acid regulates critical proinflammatory pathways in VSMCs, suggesting it may have a role in the vascular changes associated with hypertension and vascular disease.

Uric Acid Stimulates Monocyte Chemoattractant Protein-1 Production in Vascular Smooth Muscle Cells Via Mitogen-Activated Protein Kinase and Cyclooxygenase-2

Cardiomyocytes of the failing heart undergo profound phenotypic and structural changes that are accompanied by variations in the genetic program and profile of calcium homeostatic proteins. The und...

Stanniocalcin-1 is a naturally occurring L-channel inhibitor in cardiomyocytes: relevance to human heart failure.

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Uric Acid Stimulates Monocyte Chemoattractant Protein-1 Production in Vascular Smooth Muscle Cells Via Mitogen-Activated Protein Kinase and Cyclooxygenase-2

Stanniocalcin-1 is a naturally occurring L-channel inhibitor in cardiomyocytes: relevance to human heart failure.