Type 2 diabetes mellitus and hypertension are two important public health challenges, and both are linked to an increased risk of cardiovascular events. There is compelling evidence that hyperuricemia has been found to be positively related to the risk of atherosclerosis, hypertension and metabolic syndrome. However, controversy remains in epidemiological population studies. In this study, we found that SUA levels were higher in males than in females, which is comparable with the findings of other authors. We also found that males had higher levels of other factors associated with metabolic disorders, such as glucose and lipids. The association between hypertension and SUA was independent of other factors. This independent association also included sex, BMI, WBC, TG and HDL, excluding TC and LDL (data not shown).
Based on prospective cohort studies involving 55607 subjects, hypertension risk was found to increase by 13% for every 1 mg/dL increase in serum SUA level. Elevated blood uric acid was observed in 89% of adolescents with primary hypertension in the early stage . Another later study also had a similar finding . A randomized double-blind clinical study found that allopurinol (an inhibitor of uric acid synthesis in vivo) reduces blood pressure in asymptomatic hyperuricemia . This indicates that hyperuricemia may increase cardiovascular risk during asymptomatic periods. Therefore, whether asymptomatic hyperuricemia needs treatment is an urgent problem to be solved in the future management of hypertension. Further studies are needed to determine whether there is a threshold for the effect of serum urate on blood pressure.
In this study, according to the quartile analysis of uric acid, it was found that the levels of TC, TG, LDL-C FBG and WBC were also higher with an increase in uric acid. The change in HDL showed an obviously opposite trend. SBP and DBP proved to be higher with more factors of metabolic disorders. This evidence indicated that uric acid might increase the risk for metabolic syndrome. In addition, a cross-sectional study involving 4053 patients demonstrated that individuals with hyperuricemia were also accompanied by a higher risk of insulin resistance and diabetes. The risk of cardiovascular disease due to hyperuricemia may be a secondary effect of uric acid, which presents as a higher BMI, TG and fasting insulin and lower HDL-C. Of course, some studies do not fully support this view. A clinical study including 3508 subjects without clinical cardiovascular disease revealed that high SUA levels were associated with increased triacylglycerol/high-density lipoprotein and hepatic steatosis, independent of metabolic syndrome and obesity . Choi et al. found that uric acid promoted fat synthesis in the liver in an ER stress-induced manner . Uric acids have also been suggested to play a role in hyperglycemia. Rats with oxyacid-induced hyperuricemia have an increased metabolic response to fructose and increased blood glucose, blood pressure and kidney damage . Another study also reported that hyperuricemic rats exhibited increased liver fat accumulation through elevated hepatic aldose reductase expression .
Urate may induce the occurrence and development of hypertension through a variety of potential underlying mechanisms. Several recent studies mentioned the observation of urate crystal deposits in the joints of the majority of asymptomatic hyperuricemic patients, which may promote chronic inflammation . Soluble uric acid activates the NLRP3 inflammasome and the assembly of NLRP3 and apoptosis-associated speck-like protein in macrophages, even at low concentrations of 300 µmol/L. In addition, then, the level of IL-1β increases . The stimulation of urate increases the expression of c-reactive protein in human umbilical vein endothelial cells and smooth muscle cells . Another study found that soluble urate induced reactive oxygen species increases in human umbilical vein endothelial cells . Urate may promote endothelial dysfunction by nitric oxide inhibition and increasing oxidative stress. Meanwhile, urate stimulates proliferation, angiotensin II production and oxidative stress mediated by the MAP kinase pathway in vascular smooth muscle cells . This proliferative effect may be involved in vascular remodeling. Animal model studies of hyperuricemia have revealed that hyperuricemic rats show proteinuria and reduced renal function microvascular injury and macrophage infiltration[31, 32].
We noted some limitations to our study. First, we do not seem to know for sure whether uric acid was the "cause" of hypertension because this was a cross-sectional study. Second, almost all the research subjects were employees of the Dongfeng Commercial Vehicle Company and of Han nationality. Therefore, our findings may not apply to other ethnic groups with different genetic backgrounds. More prospective cohort studies need to be performed to confirm the cause-effect relationship between SUA and hypertension. Basic research on urate and its influencing mechanism on hypertension is still a matter of debate in this field.
In conclusion, we verified that uric acid was associated with hypertension independent of other metabolic risk factors. However, the presence of other risk factors with uric acid had an additive effect on blood pressure. Therefore, routine control of SUA is recommended in the management of hypertension to reduce long-term risk.