Uric acid and the Origins of Hypertension

The twentieth century witnessed an explosive increase in the frequency of obesity, hypertension and diabetes in the US, affecting 34%, 29%, and 12% of the adult population, respectively (1–3). Children and adolescents were not immune to this epidemic, and the marked rise in obesity in children has been accompanied by marked increases in conditions that were once rare in this age-group, such as primary hypertension, “adult-onset” type 2 diabetes, metabolic syndrome and nonalcoholic fatty liver disease (NAFLD), and even premature cardiovascular disease (4–6).

While the emergence of hypertension and type 2 diabetes in childhood is alarming, it provides a unique opportunity for those interested in origins of disease. The short duration leading to the development of the disease, the still relative infrequency of the condition, and the reduced number of other comorbidities in the pediatric population provides an opportunity to better define risk factors and pathophysiology. It seems highly likely that the etiology of hypertension will be first identified in children, and that the first treatments aimed at effective prevention or mechanism-based cure will also involve children. In this article, we review studies that aim to identify the etiology of hypertension in this epidemic. We will focus on uric acid as the “dark horse” that is rapidly becoming a major contender for driving hypertension.

Uric acid: General Considerations

Uric acid is a product of purine metabolism that circulates in the blood and is recognized as a cause of gout (from urate crystal precipitation in joints) and kidney stones (from urate crystals). In most mammals serum uric acid levels are relatively low (1–3 mg/dl) due to the presence of an enzyme in the liver, uricase, that degrades uric acid to eventually produce allantoin. However, the great apes and humans lost uricase due to a mutation 15 million years ago. For apes, and humans living on native diets, serum uric acid levels are in the 3 to 4 mg/dl range (7–8). However, there has been a progressive rise in serum uric acid levels over the last 100 years associated with the rise in obesity and the western diet (7–8). The reason for the increasing serum uric acid levels may relate both to increased intake of foods known to raise uric acid levels, such as fructose-containing sugars and purine-rich foods (9–10). The most common sources of fructose are from added sugars (sucrose and high fructose corn syrup) and soft drinks and fruit juices are the richest source, amounting to 7% of the average American diet, and up to 15% of total caloric intake in adolescents (11). Purine-rich foods can also raise uric acid, of which beer, shellfish, and organ meats are primary sources. In addition, obesity, insulin resistance, and kidney disease may also increase uric acid levels (12).

Historically, serum uric acid was not considered important other than for carrying increased risk for developing gout and kidney stones. However, it has been known since the 1800s that elevations of serum uric acid are common in subjects with hypertension, obesity, metabolic syndrome, type 2 diabetes, chronic kidney disease, and heart disease (13). Until recently, it was thought that the reason an elevated uric acid is common in these conditions is because the risk factors associated with heart disease, such as obesity and insulin resistance, are also risk factors for gout (14). As such, serum uric acid has not been considered a true cardiovascular risk factor and is not routinely measured in subjects at cardiovascular risk, and nor is treatment of asymptomatic hyperuricemia currently recommended (15–16). Recent studies, however, suggest the possibility that an elevated uric acid may not only be a true risk factor, but that it may be one of the most important risk factors for cardiovascular disease.

Uric acid and Hypertension

Experimental Studies

Renewed interest in the role of uric acid in hypertension occurred when it was observed that rats made hyperuricemic by a uricase inhibitor developed hypertension (17). The hyperuricemic rats developed all of the hemodynamic findings observed in essential hypertension, including prominent vascoconstriction of the afferent arteriole, with a reduction in renal blood flow and a relative preservation of the GFR (18). Histologic studies also showed lesions similar to that observed in essential hypertension, with thickening of the afferent arteriole (arteriolosclerosis) and mild tubulointerstitial injury and inflammation (17, 19).

Subsequent studies showed that the hypertension developed in two phases. Initially, the hypertension could be directly reversed by reducing uric acid levels with either xanthine oxidase inhibitors or uricosuric agents (17). Hypertension during this phase was mediated by uric acid-dependent activation of the renin angiotensin system, by the induction of oxidative stress, and by the development of endothelial dysfunction with a reduction in endothelial nitric oxide levels (17, 19–21). During this initial phase hyperuricemic hypertension could be observed even under the presence of a low salt diet. Over time, however, the animals developed significant renal microvascular disease and tubulointerstitial inflammation, and the hypertension became kidney-dependent, salt-sensitive, and persisted despite allowing uric acid levels to return to baseline (22).

The observation in this model that hypertension consists of two phases parallels what is commonly observed in humans. Early hypertension is often associated with high serum uric acid levels, high serum renin, poor endothelial function, and salt-resistance (hypertension that is not affected by restriction in salt) (reviewed in (23)). Over time, however, hypertension becomes increasingly salt-sensitive. Experimental studies suggest that the development of salt-sensitive hypertension is dependent on renal microvascular disease and low-grade renal inflammation associated with persistent renal vasoconstriction and renal ischemia (24). Recent studies suggest a key role for the intrarenal T cell infiltration in driving this response, and that these cells release oxidants and angiotensin II that maintain the renal vasoconstriction and cause a relative impairment in sodium excretion that characterizes the hypertensive phenotype (25–26).

Subsequently uric acid was found to induce a wide variety of biological effects on cells in culture. Uric acid was originally thought to induce inflammation primarily as a consequence of forming crystals and activating inflammasomes (27), but soluble uric acid was found to enter cells via specific transporters where it could activate signaling mechanisms that stimulates the release of inflammatory mediators, vasoconstrictive substances, proliferative growth factors, and oxidants (19, 22, 28–46) and induce mitochondrial dysfunction (47–48).

The observation that uric acid could induce oxidative stress in a variety of cell types (34–37, 47–49) may appear incongruent with the known ability of uric acid to function as an antioxidant (50–55). However, while uric acid may function as an antioxidant against extracellular-induced oxidative stress, when uric acid enters cells it induces an oxidative burst that appears to be mediated by an increase in NADPH oxidase (37, 47). How this occurs remains unknown, but we do know that the inactivation of peroxynitrite by uric acid is not completely benign, as the reaction generates both radicals (including aminocarbonyl radical and triuretcarbonyl radical) and alkylating species (56–57). Evidence that this reaction is occurring in humans has been shown, both in preeclampsia and also in response to the oxidative stress associated with smoking (56, 58).

Clinical Studies

Experimental studies suggest that uric acid might have a role in initiating the development of hypertension, and that over time the importance of the serum uric acid would shift more to the role of the kidney in maintaining a salt-sensitive hypertensive state. Consistent with this hypothesis, an elevated serum uric acid has been found to predict consistently the development of hypertension (Table), including two meta-analyses (59–60). An elevated uric acid in childhood also predicts hypertension as an adult (61). Few other risk factors carry such power or reproducibility.

Table.

Serum Uric acid as a Predictor of Hypertension

Study	Population	F/U	Independent	Year	(Ref)
Israeli Heart Study	10,000 males	5 YRS	Not done	1972	(112)
Kaiser Permanente	2,062 subjects	6 YRS	Yes	1990	(113)
Univ of Utah	1482 adults	7 YRS	Yes	1991	(114)
Olivetti Heart Study	619 males	12 YRS	Yes	1994	(115)
CARDIA study	5115 adults	10 YRS	Yes	1999	(116)
Osaka Health Survey	6,356 males	10 YRS	Yes	2001	(117)
Hawaii-Los Angeles-Hiroshima	140 males	15 YR	Yes	2001	(118)
Osaka Factory Study	433 males	5 YR	Yes	2003	(98)
Osaka Health Survey	2310 males	6 YRS	Yes	2003	(119)
Okinawa	4489 adults	13YRS	Yes	2004	(120)
Bogalusa Heart	679 children	11 YRS	Yes	2005	(61)
Framingham	3329 adults	4 YRS	Yes	2005	(121)
Normative Aging Study	2062 males	21 YRS	Yes	2006	(122)
ARIC	9,104 adults	9 YRS	Yes	2006	(123)
Beaver Dam	2,520 adults	10 YRS	Yes	2006	(124)
MRFIT	3073 men	6 YRS	Yes	2007	(125)
Health Professional Followup	750 men	1 8 YRS	No	2007	(126)
Nurse Health Study	1500 women	5 YRS	Yes	2009	(127)
China	7,220 adults	4 YRS	Yes	2009	(60)
USA	141 children	3 YRS	Yes	2009	(128)
Italy	1,410 young adults	20 YRS	Yes	2010	(129)
GOCADAN	1,078 Adults	6 YRS	Yes	2012	(130)
NHANES Continuous	6,036 adolescents	8 YRS	Yes	2012	(71)
Cardia	4.752 adults	20 YRS	Men	2012	(131)

An elevated serum uric acid is also common in subjects with prehypertension (62–64), with new onset hypertension (65), with gestational hypertension (66), and with advanced hypertension (67). One study in adolescents found that 90 percent of primary hypertension was associated with high (>5.5 mg/dl) serum uric acid levels, whereas uric acid was not elevated in secondary hypertension (65). Other studies have also linked hyperuricemia with hypertension in adolescents (68–70). More recently a study of 6036 adolescents (12 to 17 years old) from the National Health and Nutrition Examination Survey (1999–2006) found that a serum uric acid of >5.5 mg/dl carried a two-fold greater risk for having hypertension, and that for every 0.1 mg/dl change in uric acid the risk for hypertension increased by 38 percent (71). In contrast, the association of serum uric acid decreases in the elderly, and is no longer present in subjects over 90 years of age (72).

Pilot studies also suggest that lowering uric acid can result in an improvement in blood pressure in obese adolescents with hyperuricemia and prehypertension (73), in adolescents with newly diagnosed hypertension (74), and in adults with asymptomatic hyperuricemia (75–76). In these studies the greatest effect of lowering uric acid on blood pressure has been observed in adolescents. In a recent study of obese prehypertensive adolescents, Soletsky and Feig showed that both allopurinol (a xanthine oxidase inhibitor) or probenecid (a uricosuric) had marked effects on both ambulatory systolic (mean decrease of 9.2 and 8.9 mm Hg, respectively, p< 0.004) and diastolic (mean decrease of 6.1 and 7.3 mm Hg, respectively, p<0.007) blood pressures, respectively (73). In a study of 30 adolescents with newly diagnosed stage 1 essential hypertension, 21 of 30 patients normalized their blood pressure with urate lowering therapy in comparison with 1 of 30 while on placebo. Of the nine patients who did not respond, only 2 succeeded in attaining serum uric acid <5.5mg/dL, so 21/23 subjects who normalized serum uric acid with therapy also normalized blood pressure. [55] Clearly more studies need to be done, but these data suggest that hyperuricemia may be one cause, and possibly a major cause, of hypertension, at least in adolescents.

How Does the Uric Acid Story Relate to the Fetal Programming Hypothesis?

A favored hypothesis for the development of hypertension is the concept of “fetal programming”, which suggests that alterations in the fetus during pregnancy might lead to increased susceptibility to hypertension later in life. This hypothesis was initiated by the observation by Barker that babies born with low birth weight (especially low birth weight for gestational age) are at risk for developing hypertension in adulthood (77). Subsequent studies suggest that fetal stress, such as induced by maternal malnutrition, might lead to epigenetic adaptations that may lead to increased risk not only for hypertension, but also for obesity and diabetes later in life (78–80). Another theory is that the kidney may be particularly vulnerable to fetal malnutrition as it is one of the last organs to develop, and that this may result in reduced nephron formation, that might lead to kidneys with fewer glomeruli and greater predisposition for acquiring defects in sodium excretion and developing hypertension (81). Some studies suggest that hypertensive individuals not only tend to have lower birth weights, but also fewer glomeruli (82).

Interestingly, uric acid may have a role in both causing low birth weights and also increasing the risk for the later development of hypertension (43). One of the extreme examples where fetal programming may be important is in preeclampsia, in which placental ischemia results in fetal distress and a marked increased risk for low birth weight infants. In subjects with preeclampsia serum uric acid is often markedly elevated and strongly predicts fetal distress and low birth weight (83–84). Uric acid is a small molecule that freely passes from the maternal to fetal circulation (85). Because uric acid can block endothelial cell proliferation and function (31, 39, 43), it is possible that it may have a role in blocking fetal growth and kidney development. Indeed, studies in pregnancy have shown that women who have higher uric acid levels, even if normotensive, are at increased risk for small infants (86). Studies have also shown that an elevated uric acid in amniotic fluid obtained during the second trimester also predicts small infant birth weight (87).

Small birth weight infants also have higher serum uric acid levels at birth (85, 88) which persists throughout childhood (89–92). Interestingly, children with low birth weights also manifest endothelial dysfunction and higher blood pressure in association with their higher serum uric acid levels (89–92). In our study of adolescents presenting with hypertension, we also confirmed that these individuals who were commonly hyperuricemic also had low birth weights (65).

The reason low birth weight is associated with elevated uric acid levels is not completely evident. One possibility is that familial factors may be involved. For example, diets high in fructose are associated with the development of hyperuricemia (10) and hypertension (93), and have been linked with the risk for preeclampsia and small birth weight infants (94–95). As such, if such diets are common in the parents, it may carry over to the children; indeed, soft drink intake is associated with high uric acid levels and hypertension in children (69). It is also possible that a reduced nephron number may alter urate excretion, or that genetic factors may also be involved. For example, one study has reported that polymorphisms in urate transport involving SLC2A9 can increase the risk for hypertension (96). Regardless, the data suggests a strong relationship of uric acid with birth weight and the risk for hypertension as an adult.

The Relationship of Uric acid with Obesity, Diabetes and Kidney Disease

While the hypothesis that uric acid may have a role in driving hypertension is especially strong, there is also increasing evidence that uric acid may have causal roles in obesity, insulin resistance and chronic kidney disease (reviewed in (97)). Indeed, serum uric acid has been found to be a strong independent predictor for the development of obesity, diabetes, nonalcoholic fatty liver disease and chronic kidney disease (98–101), and experimental studies have identified mechanisms by which uric acid may drive these conditions (30, 42, 44, 49). In these studies, one of the more common mechanisms involves the intracellular generation of uric acid in response to fructose from added sugars (102).

Challenges to the Uric acid Hypothesis

Several arguments have been raised against the uric acid hypertension hypothesis. One is that the ability of xanthine oxidase inhibitors to reduce blood pressure may related more to the use of these inhibitors rather than the lowering of uric acid. Xanthine oxidase inhibitors not only lower uric acid, but also block oxidants generated during the xanthine oxidase reaction. These agents also raise xanthine and hypoxanthine levels and may also have other effects unrelated to lowering of uric acid. In support of this possibility is the observation that endothelial dysfunction is consistently improved in humans by lowering uric acid with xanthine oxidase inhibitors, but no improvement in endothelial function was observed in the one study in which uric acid was lowered by the uricosuric, probenecid (103). Furthermore, xanthine oxidase polymorphisms linked with oxidative stress are associated with an increased risk for hypertension (104). However, the observation that uric acid induces a wide variety of proinflammatory and vasoconstrictive effects on various cell types (19, 22, 28–49) and that lowering uric acid with probenecid can reduce blood pressure in obese prehypertensive adolescents (73) would suggest that uric acid likely is a contributor to hypertension. It seems likely that the reason xanthine oxidase inhibitors are better than uricosurics relates to the superior ability of the former to block intracellular uric acid generation. It is also possible that blocking xanthine oxidase-associated oxidants is an added benefit to the use of this class of drugs.

A second argument is that subjects with genetic polymorphisms in urate transport that are associated with higher uric acid levels have an increased risk for gout but not hypertension (105–106). This would suggest that serum uric acid itself is not likely the driver of the hypertensive response. However, our studies suggest that while gout is driven by extracellular uric acid and its predisposition for precipitating into crystals, the mechanism(s) by which uric acid induces hypertension is via its ability to enter cells and induce vasoconstrictive and proinflammatory responses (19, 22, 28–49). In this regard, the genetic polymorphisms that are primarily linked with high serum uric acid levels relate to transporters that increase the export of uric acid from cells into the circulation (105), and hence we would predict that these polymorphisms would not necessarily predict the development of hypertension.

Another argument is that the acute infusion of uric acid into humans is associated with an immediate improvement in endothelial function (107). Again, this might be explained by the strong ability of uric acid to act as an antioxidant in the extracellular environment.

A fourth argument is that the studies using the uricase inhibitor (oxonic acid) must be viewed with caution, as these agents may have additional effects besides raising uric acid levels. Nevertheless, the observation that two different classes of drugs (uricosurics and xanthine oxidase inhibitors) can improve blood pressure in oxonic acid-treated rats suggest it is the uric acid that is responsible for the hypertension.(17, 108–109)

It is also important to recognize that not all subjects with hypertension have an elevated uric acid, as we are only suggesting that hyperuricemia may be one cause of hypertension. Likewise, there are subjects who have an elevated uric acid in the absence of hypertension. These individuals may have other genetic or environmental factors that may protect them from the effects of uric acid, such as excellent endothelial or antioxidant function. Indeed, rats that are hyperuricemic are protected from hypertension when antioxidants or L-arginine (which stimulates endothelial NO production) are administered (20–21). However, subjects with asymptomatic hyperuricemia are at risk for developing hypertension, even when no other cardiovascular or metabolic risk factors are present (Table).

In March 1882, Robert Koch presented his thesis that tuberculosis was driven by a specific mycobacterium. Today, the adaptation of Koch’s postulates has often been used to provide evidence for causality. In the case of uric acid, there is now compelling evidence that uric acid may have a causal role in some forms of hypertension. An elevated serum uric acid independently predicts the development of hypertension (Table). Adolescents presenting with hypertension often have an elevated serum uric acid (65). Raising uric acid in animals with a uricase inhibitor results in hypertension by inducing oxidative stress, endothelial dysfunction, and activation of the renin angiotensin system (17, 20–21). In pilot studies the lowering of uric acid results in the lowering of blood pressure, especially in adolescents (73–76). Nevertheless, it important for the findings from the pilot studies to be confirmed by large clinical trials. In addition, there are also safety concerns with using xanthine oxidase inhibitors. Allopurinol, for example, has been associated with the development of a Stevens-Johnson-like syndrome (110). There is some evidence that those subjects who are at risk for this allopurinol hypersensitivity syndrome carry HLA-B58 (111), raising the possibility that screening for this HLA antigen may be a way to reduce this serious complication. Regardless of whether the lowering of uric acid becomes a treatment option for hypertension in the future, the studies of uric acid have provided new insights into the pathogenesis of this important disease.