This Article Abstract Full Text (PDF) All Versions of this Article: 40/3/355    most recent 01.HYP.0000028589.66335.AAv1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Watanabe, S. Articles by Johnson, R. J. Search for Related Content PubMed PubMed Citation Articles by Watanabe, S. Articles by Johnson, R. J. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Dietary Sodium Related Collections Genetics of cardiovascular disease

(Hypertension. 2002;40:355.)
© 2002 American Heart Association, Inc.

Hypothesis Paper

Uric Acid, Hominoid Evolution, and the Pathogenesis of Salt-Sensitivity

Susumu Watanabe; Duk-Hee Kang; Lili Feng; Takahiko Nakagawa; John Kanellis; Hui Lan; Marilda Mazzali; Richard J. Johnson

From the Division of Nephrology, Baylor College of Medicine, Houston, Tex.

Correspondence to Richard J. Johnson, MD, Division of Nephrology, Baylor College of Medicine, SM-1273, 6550 Fannin St, Houston, TX 77030. E-mail rjohnson{at}bcm.tmc.edu

	Abstract

Top Abstract Introduction Parallel Mutations in the... Uric Acid Maintains Blood... Hyperuricemia Induces Salt... Uric Acid Stimulates Smooth... Uric Acid: Potential Role... Perspectives References

 
Humans have elevated serum uric acid as a result of a mutation in the urate oxidase (uricase) gene that occurred during the Miocene. We hypothesize that the mutation provided a survival advantage because of the ability of hyperuricemia to maintain blood pressure under low-salt dietary conditions, such as prevailed during that period. Mild hyperuricemia in rats acutely increases blood pressure by a renin-dependent mechanism that is most manifest under low-salt dietary conditions. Chronic hyperuricemia also causes salt sensitivity, in part by inducing preglomerular vascular disease. The vascular disease is mediated in part by uric acid-induced smooth muscle cell proliferation with activation of mitogen-activated protein kinases and stimulation of cyclooxygenase-2 and platelet-derived growth factor. Although it provided a survival advantage to early hominoids, hyperuricemia may have a major role in the current cardiovascular disease epidemic.

Key Words: uric acid • hypertension, sodium-dependent • renal disease • mutation

	Introduction

Top Abstract Introduction Parallel Mutations in the... Uric Acid Maintains Blood... Hyperuricemia Induces Salt... Uric Acid Stimulates Smooth... Uric Acid: Potential Role... Perspectives References

 
Cardiovascular disease and hypertension are epidemic in modern society. Cardiovascular disease is the number one cause of death in the United States, claiming nearly 1 million lives yearly and accounting for 40% of all-cause mortality and more deaths than the next 7 leading causes combined.¹ The most common form of cardiovascular disease is hypertension, which is present in approximately 20% of the population (50 million people) in the United States and whose frequency increases dramatically with age, affecting the majority of the population over the age of 60.^2,3 Hypertension markedly increases the risk for myocardial infarction, stroke, congestive heart failure, peripheral vascular disease, and end-stage renal disease.^4,5 Treatment of hypertension reduces these complications and can reduce the number of cardiovascular deaths as well as improve overall quality of life.^6,7

There is evidence that the increased prevalence of hypertension is a recent event in human history and that it correlates with changes in the diet with industrialization⁸. Dahl⁹ and Tobian¹⁰ have suggested that a key nutritional factor that may account for the increased prevalence of hypertension in industrialized societies is the dietary sodium intake. Primitive societies, such as the Yanomamo, whose populations ingest a very small amount of sodium, have an absence of hypertension.¹¹ The sodium content of early hunter-gatherers of the Paleolithic Period was also extremely low and has been estimated to be only 690 mg/d (equivalent to 30 mEq Na⁺ or 1.9 g NaCl).¹² In contrast, the average sodium intake in the current American diet averages 4000 mg/d (170 mEq Na⁺ or approximately 10 g NaCl). Although individuals with normal kidneys might be able to excrete the increased sodium content without altering systemic blood pressure, there is evidence that individuals who develop essential hypertension have a relative defect in their ability to excrete sodium.¹³ It has thus been speculated that the sudden increase in sodium content in the diet of industrialized nations will "unmask" those individuals with this physiological renal defect and thereby precipitate the development of hypertension.¹⁰ We now present a hypothesis that the development of salt sensitivity in humans may be related to environmentally driven mutations of the urate oxidase (uricase) gene, which occurred during the Miocene. The mechanism relates to an increase in serum uric acid (urate), which we have previously shown to regulate blood pressure^14,15 and, in this paper, will show to induce salt sensitivity.

	Parallel Mutations in the Uricase Gene in Early Hominoids: Evolutionary Implications

Top Abstract Introduction Parallel Mutations in the... Uric Acid Maintains Blood... Hyperuricemia Induces Salt... Uric Acid Stimulates Smooth... Uric Acid: Potential Role... Perspectives References

 
Uric acid is generated during the metabolism of purines and in most mammals is further degraded to allantoin by the hepatic enzyme, uricase (urate oxidase), resulting in serum uric acid levels in the range of 0.5 to 1.5 mg/dL. In contrast, serum uric acid is higher in hominoids (apes and humans) as well as in certain New World monkeys. The increase in uric acid is due to distinct mutations in the uricase gene that made it nonfunctional. In humans, the chimpanzee (Pan), and the gorilla (Gorilla), 3 mutations have been identified, including a nonsense mutation of codon 33, a nonsense mutation of codon 187, and a splice mutation in exon 3.¹⁶ The mutation at codon 33 is also present in the orangutan (Pongo). In contrast, none of these mutations are present in the gibbon (Hylobates), whereas a separate 13 bp deletion was identified between codons 72 and 76 of exon 2.¹⁶ Based on the phylogeny of hominoid evolution as assessed by DNA-DNA hybridization,^17,18 Wu et al¹⁶ proposed that the nonsense mutation at codon 33 occurred between 24 and 13 to 16 million years ago (affecting the Pongo/Gorilla/Pan/Homo lineage) and the 13 bp deletion in exon 2 occurred sometime after the split (ie, divergence node) of the Hylobates from the other hominoids, which occurred around 22 to 24 million years ago (Figure 1).

View larger version (12K): [in this window] [in a new window]   Figure 1. Cladogram of hominoid evolution showing the proposed times of the various uricase mutations. The divergence nodes for the Cercopithecoidea are 27 to 33 million years ago (MYA), gibbons 18 to 22 MYA, orangutans 13 to 16 MYA, gorilla 8 to 10 MYA, chimpanzees/man 4.9 to 7.7 MYA. (Adapted with permission from Wu et al,16 Journal of Molecular Evolution, 1992, 34:78–84, © Springer-Verlag GmbH.)

The uricase gene is also altered within the New World (Ceboidea) and Old World (Cercopithecoidea) monkeys.¹⁹ Serum uric acid was found to be elevated in several species of New World monkeys, including the tamarin (Saguinus), the capuchin (Cebus), and the wooly monkey (Lagothrix), whereas uric acid was low in the squirrel monkey (Saimiri) and owl monkey (Aotus).¹⁹ The levels of uric acid correlated with changes in hepatic urate oxidase activity in these species. Although studies determining the site of the mutations responsible for the loss of uricase in the New World monkeys have not been performed, the mutations were likely independent from those observed during hominoid evolution, given evidence that the divergence of the Platyrrhini infraorder (the New World monkeys) from the Catarrhini (Old World monkeys and hominoids) occurred approximately 40 million years ago.²⁰ Interestingly, although urate oxidase was retained in the Old World monkeys (Cercopithecoidea), the enzyme activity is relatively unstable compared with other mammalian (nonprimate) species, suggesting that evolutionary mechanisms that impair urate oxidase activity may also have been operative in this superfamily.^19,21

The observation that several independent mutations involving uricase occurred during hominoid evolution and in parallel during the evolution of the Old World and New World monkeys has been interpreted as evidence that there must have been an evolutionary advantage for early primates in having an elevated uric acid level.^16,19,21 The time frame of the mutations for the uricase gene indicates that they occurred during the Miocene (24 to 8 million years ago). It is thus important to understand the environmental pressures that were occurring during this period of hominoid history.

Fossil evidence suggests that the earliest hominoids, such as Proconsul, originated in East Africa approximately 22 to 17 million years ago, where they lived in lush subtropical forests and wetlands.^22–25 These early hominoids were arboreal quadrupeds with a diet that was frugivorous (ingesting primarily soft fruits).^22–25 By the early Miocene, there were numerous hominoid species,^22,23 particularly in Eurasia.²⁵ However, by the middle to late Miocene (14 to 8 million years ago), there was an extinction of many Miocene apes, especially in Europe.^24,25 This appears to be associated with an environmental change to a drier and more seasonal climate and with a change in the habitat to more open areas of savannas interspersed with tropical and subtropical forests.²⁵ In certain areas of East Africa, wet and wooded habitats may have been maintained.²⁶ Molecular DNA studies suggest that there was a rapid period of positive selection for various genes during this period, particularly for a gene family (morpheus) in the short arm of chromosome 16, ²⁷ and there were significant changes in dentition and axial skeleton that may have facilitated adaptation to a more arid environment.^22,23,28

As discussed above, the sodium intake of the early hunter-gatherers in the middle to late Pleistocene was in the range of 690 mg (1.9 g NaCl) per day. The sodium intake of early hominoids during the Miocene epoch (from 24 to 5 million years ago) was likely even lower, because the diets consisted primarily of fruits (frugivorous) or leaves (foliverous). Eaton and Konner estimated that the sodium content of a strictly vegetarian Paleolithic diet may have amounted to only 225 mg sodium (10 mEq Na⁺ or 0.6 g NaCl).¹² Thus, the climatic shift to more arid conditions in the middle to late Miocene may have placed selection pressure on the early primates toward a genotype that would maximally conserve sodium with the maintenance of blood pressure.

	Uric Acid Maintains Blood Pressure Under Low-Sodium Conditions

Top Abstract Introduction Parallel Mutations in the... Uric Acid Maintains Blood... Hyperuricemia Induces Salt... Uric Acid Stimulates Smooth... Uric Acid: Potential Role... Perspectives References

 
Most authorities^16,19,21 have proposed that the mutations in the uricase gene provided an evolutionary advantage because uric acid may function as an antioxidant.²⁹ Although an antioxidant role for uric acid may be one mechanism to explain the beneficial effects of the uricase mutation, we examined the hypothesis that uric acid might regulate blood pressure. This hypothesis was based on previous studies demonstrating that serum uric acid correlates with blood pressure and predicts the development of hypertension in population-based studies.^30–32

To test this hypothesis, mild hyperuricemia was induced in rats by administering the uricase inhibitor, oxonic acid, and then, to recreate the prehistoric conditions, we placed the rats on a low-salt (0.125% NaCl) diet.^14,15 Normal rats on a low-salt diet have either no change or a gradual fall in blood pressure; in contrast, hyperuricemic rats increase their blood pressure (Figure 2).¹⁴ The increase in blood pressure correlated with the uric acid levels and could be prevented by lowering the uric acid levels with allopurinol (a xanthine oxidase inhibitor) or with benziodarone (a uricosuric agent). The increase in blood pressure in hyperuricemic rats was shown to be mediated in part by stimulation of the renin angiotensin system.¹⁴ This hormonal system has a key role in maintaining blood pressure, glomerular filtration rate, and sodium balance under low-salt dietary conditions. We also found that hyperuricemic rats develop vascular disease, particularly of the afferent arteriole of the renal microvasculature, as well as mild renal interstitial inflammation and tubular injury.^14,15 These renal lesions, as well as the renin activation, could be prevented by lowering the uric acid with either allopurinol or benziodarone. The arteriolar lesion resembled the arteriolosclerosis observed in patients with essential hypertension, but the lesion occurred independently of blood pressure as a consequence of a direct stimulation of the vascular smooth muscle cells by uric acid.¹⁵

View larger version (19K): [in this window] [in a new window]   Figure 2. Hyperuricemia maintains blood pressure under low-salt dietary conditions in the rat. Sprague-Dawley rats (n=6) placed on a low Na+ diet (0.125% NaCl) have a gradual fall in blood pressure, whereas blood pressure is increased in rats (n=6) on a low-salt diet (LSD), which are administered the uricase inhibitor, oxonic acid (OA, 2%). The administration of allopurinol (150 mg/L in the drinking water, n=6) prevents the development of the hyperuricemia and the increase in blood pressure. Uric acid levels at 7 weeks: 2.1±0.2 mg/dL, oxonic acid; 1.3±0.2 mg/dL, low-salt control; 1.2±0.3 mg/dL, oxonic acid+allopurinol.

Goldblatt originally postulated that primary renal microvascular disease might be the major pathogenic mechanism for essential hypertension.³³ Recent studies support this hypothesis.³⁴ The induction of preglomerular arteriolar disease in experimental models leads to tubular ischemia, the interstitial infiltration of lymphocytes and macrophages, local oxidant generation, and alterations in the expression of vasoconstrictors and vasodilators that favor local vasoconstriction.³⁴ These changes result in both a decrease in sodium filtration (caused by a decrease in the ultrafiltration coefficient, Kf) and increased sodium reabsorption (via direct tubular effects) and result in an enhanced blood pressure response to sodium (salt sensitivity).³⁴

	Hyperuricemia Induces Salt Sensitivity in Rats

Top Abstract Introduction Parallel Mutations in the... Uric Acid Maintains Blood... Hyperuricemia Induces Salt... Uric Acid Stimulates Smooth... Uric Acid: Potential Role... Perspectives References

 
Given that hyperuricemia induces primary renal arteriolar lesions, we hypothesized that chronic hyperuricemia might also induce salt sensitivity. The uricase inhibitor, oxonic acid (2%), was administered with a low-salt diet to rats for 7 weeks. The diet resulted in mild hyperuricemia (uric acid level at 1 week of 2.4±0.7 versus 1.2±0.1 mg/dL in low-salt diet controls, P<0.005, 6 rats tested per group). The oxonic acid diet was then stopped and rats continued on a low-salt diet for 2 weeks, allowing the serum uric acid levels to decrease to levels no different from those observed in low-salt diet controls. Renal tissue obtained from a random subset of rats sacrificed at 9 weeks showed that the previously hyperuricemic rats had a persistent afferent arteriolopathy, with decreased arteriolar lumen diameter and an increased media:lumen ratio compared with low-salt diet controls (Table 1). The rats also showed mild interstitial inflammation and low-grade interstitial collagen deposition (Table 1). Rats were then randomized to a low- or high-salt (2% NaCl) diet. An increase in blood pressure from the high-salt diet (ie, salt sensitivity) was observed only in the rats that had been previously hyperuricemic (Figure 3). This experiment therefore demonstrates that hyperuricemia in the rat can induce salt sensitivity and is consistent with other models in which salt sensitivity can be induced as a consequence of the development of preglomerular arteriolar disease.³⁴

View this table: [in this window] [in a new window]   Table 1. Hyperuricemia Induces Preglomerular Microvascular Disease and Interstitial Inflammation

View larger version (20K): [in this window] [in a new window]   Figure 3. Hyperuricemia induces salt sensitivity. Sprague-Dawley rats were administered oxonic acid (2%) on a low-salt (0.125% NaCl) diet for 7 weeks (OA-LS group). During this time blood pressure increased compared with low-salt diet (LS) controls. The oxonic acid diet was then stopped, allowing uric acid levels to return to levels equivalent to the low-salt controls. At 9 weeks rats were randomized to continue their low-salt diet or switched to a high-salt (2% NaCl) diet (HS). Previously, hyperuricemic rats developed an increase in blood pressure documenting the development of salt sensitivity; no change in blood pressure was observed in the control group on switching to a high-salt diet. n=6 per group; #P<0.05 versus LS by Student t test; *P<0.05 versus other groups by ANOVA with Fisher exact test.

	Uric Acid Stimulates Smooth Muscle Cell Proliferation

Top Abstract Introduction Parallel Mutations in the... Uric Acid Maintains Blood... Hyperuricemia Induces Salt... Uric Acid Stimulates Smooth... Uric Acid: Potential Role... Perspectives References

 
We further explored the mechanism by which uric acid causes vascular disease. Soluble, endotoxin-free uric acid (3 to 5 mg/dL) stimulates vascular smooth muscle cell proliferation with activation of the mitogen-activated protein (MAP) kinase extracellular signal-regulated kinase (Erk1/2) and stimulation of platelet-derived growth factor (PDGF) and its receptor (Figure 4). Rao et al³⁵ have also showed that uric acid induces PDGFA-chain expression and that the smooth muscle cell proliferation can be prevented with neutralizing antibodies to PDGF. We also found that the smooth muscle cell proliferation is mediated by uric acid-induced cyclooxygenase-2 (COX-2) expression with the generation of thromboxane (Duk-Hee Kang, Takahiko Nakagawa, Lili Feng, Marilda Mazzali, Susumu Watanabe, Lin Han, Luan Truong, Raymond Harris, Richard J. Johnson. Unpublished manuscript, 2002), and partially by activation of the renin angiotensin system.¹⁵

View larger version (30K): [in this window] [in a new window]   Figure 4. Uric acid induces smooth muscle cell proliferation, MAP kinase activation, and PDGF expression. Rat aortic vascular smooth muscle cells were serum starved and exposed to uric acid (3 mg/dL) for up to 96 hours. Uric acid (UA, 3 mg/dL) induces ERK1/2 MAP kinase phosphorylation. A, Uric acid (3 mg/dL) also induces PDGF-A-chain (B), C-chain (C), and -receptor (D) mRNA expression, but not PDGF-B-chain mRNA expression. A, Western blot showing the presence of phosphorylated p44 and p 42 (upper panel) and unphosphorylated p44 and p42 MAP kinase (lower panel); B through D, RNAase protection assay.

The increase in uric acid that occurred with the mutation of uricase during the Miocene may have therefore provided a survival advantage (Figure 5). The stimulation of the renin angiotensin system would be expected to acutely increase blood pressure and sodium reabsorption, whereas the preglomerular vascular disease induced by activation of MAP kinase, PDGF, and COX-2 systems would lead to chronic salt sensitivity. The net effect would be to maintain blood pressure and sodium balance.

View larger version (24K): [in this window] [in a new window]   Figure 5. Proposed mechanism by which the uricase mutation provided a survival benefit to Miocene hominoids. Environmental pressures during the middle to late Miocene resulted in a survival advantage for hominoids that could better conserve sodium and maintain blood pressure. In animals that had a mutation in the uricase gene, the increase in serum uric acid acutely increases blood pressure and maintains sodium conservation because of the action of uric acid to enhance activation of the renin angiotensin system in response to a low-salt diet. Uric acid also induces renal microvascular disease by stimulating smooth muscle cell proliferation with activation of MAP kinase and stimulation of PDGF, COX-2, and the renin angiotensin system. The development of renal microvascular disease and interstitial inflammation causes salt sensitivity and a chronic increase in blood pressure. The activation of these 2 main pathways (renin angiotensin and COX-2 and PDGF-induced microvascular disease) results in a persistent elevation in blood pressure with maintenance of sodium balance.

	Uric Acid: Potential Role in Hypertension and Cardiovascular Disease in Industrialized Societies

Top Abstract Introduction Parallel Mutations in the... Uric Acid Maintains Blood... Hyperuricemia Induces Salt... Uric Acid Stimulates Smooth... Uric Acid: Potential Role... Perspectives References

 
Whereas an elevated serum uric acid might have been advantageous for maintaining blood pressure under low-salt dietary conditions, the induction of chronic salt sensitivity would be expected to result in hypertension in modern society with its a high-salt diet. It is of interest that hyperuricemia predicts the development of hypertension and is strongly linked to cardiovascular disease.^{30–32,36,37} Serum uric acid is also higher in almost all high-risk groups, including males and postmenopausal women (because estrogen is uricosuric), in the obesity insulin-resistance syndrome (because insulin may stimulate uric acid reabsorption), in blacks, and in patients with renal disease (secondary to decreased excretion).^38,39 One might speculate that the higher uric acid levels in blacks may reflect a longer period of environmentally induced selection pressure after the deletion of the uricase gene.

Controversy has existed over the role of uric acid in cardiovascular disease for several reasons. First, some authorities have viewed hyperuricemia as a "marker" for patients at increased cardiovascular risk, as opposed to being truly pathogenic.⁴⁰ This conclusion is based on several epidemiological studies that could not show uric acid to be independent of other factors such as hypertension for predicting cardiovascular events.⁴⁰ However, a factor does not need to be independent to have a causal role in a disease process. For example, if hyperuricemia is a cause of hypertension, then it would not be expected to be independent of it as a risk factor for cardiovascular events. Evidence that uric acid may have a causal role in hypertension is suggested by the experimental studies of mild hyperuricemia in rats.^14,15 Furthermore, although hyperuricemia is not always an independent risk factor for cardiovascular events, it has always been found to be an independent risk factor for the development of hypertension.^30,31 This suggests that a causal relationship between uric acid and hypertension may in part explain the variance in epidemiological studies about the role of uric acid in cardiovascular disease.

Second, some authorities have suggested that hyperuricemia may be a secondary response to the reduced renal blood flow that is a characteristic hemodynamic finding in hypertension.⁴¹ There is strong evidence that renal vasoconstriction results in increased proximal urate reabsorption and an increase in serum uric acid.⁴² Hyperuricemia may also occur in patients with congestive heart failure or peripheral vascular disease because of tissue ischemia that increases uric acid generation (from ATP breakdown) and reduces urate excretion (caused by the effects of lactate on the organic anion exchanger). Although there is no doubt that these conditions do result in an increase in serum uric acid levels, this should not necessarily imply that the increase in serum uric acid is without biological effect. Indeed, our studies would suggest that the increase in uric acid in these conditions may well represent a feedback mechanism to augment the renin angiotensin system to maximally stimulate sodium reabsorption and maintain blood pressure, because a reduced renal blood flow and/or tissue ischemia may be signaling the organism that its overall blood volume is low.

Finally, if uric acid truly causes hypertension, one might expect evidence showing that allopurinol treatment can lower blood pressure. We have not been able to document any controlled studies that have examined this possibility. The studies to examine whether allopurinol can lower blood pressure will need to be performed carefully. Thus, as we recently reported,³⁴ once animals have significant preglomerular disease, they will manifest salt-sensitive hypertension regardless of the mechanism that causes the arteriolopathy. This was further shown in this manuscript, because we demonstrated that salt sensitivity is induced once the vascular disease occurs and that this is independent of the uric acid level. Because modern man is on a high salt diet, it may be difficult to show that lowering uric acid will lower blood pressure in subjects with hypertension. It may still be possible, however, to show this in 2 situations. First, it may be possible to show this in early hypertension associated with a marked increase in uric acid levels and before the development of significant vascular disease, such as in newly transplanted patients placed on cyclosporine or patients with preeclampsia. Second, it may be possible to show a hypotensive effect with allopurinol in patients with established hypertension who are first sodium depleted, because this will remove the salt-sensitivity mechanism mediated by the vascular disease. The sodium restriction will be necessary to remove the role of the preglomerular vascular disease in mediating the blood pressure response.

	Perspectives

Top Abstract Introduction Parallel Mutations in the... Uric Acid Maintains Blood... Hyperuricemia Induces Salt... Uric Acid Stimulates Smooth... Uric Acid: Potential Role... Perspectives References

 
We present the hypothesis that the uricase mutation that occurred during early hominoid evolution was originally advantageous because it helped to maintain blood pressure both acutely (via stimulation of the renin angiotensin system) and chronically (by inducing salt-sensitivity via the development of renal microvascular and interstitial disease). In modern society the switch to a high salt diet, coupled with this mutation, may have an important role in the current epidemic of hypertension and cardiovascular disease. Other dietary factors (such as dietary changes in potassium and magnesium) and the development of obesity are also likely to be contributory factors for the development of hypertension. Although one must be cautious in the interpretation of experimental models, we suggest that studies be performed to determine the effect of lowering uric acid in man on the development of hypertension, particularly before the development of significant microvascular and renal injury.

	Acknowledgments

 
This work was supported by National Institutes of Health grants HL-68607 and DK-52121.

Received February 12, 2002; first decision March 20, 2002; accepted June 25, 2002.

	References

Top Abstract Introduction Parallel Mutations in the... Uric Acid Maintains Blood... Hyperuricemia Induces Salt... Uric Acid Stimulates Smooth... Uric Acid: Potential Role... Perspectives References

 
1. American Heart Association. 2002 Heart and Stroke Statistical Update. Dallas, Tex: American Heart Association, 2001.

2. Burt VL, Whelton P, Roccella EJ, Brown C, Cutler JA, Higgins M, Horan MJ, Labarthe D. Prevalence of hypertension in the US adult population. Results from the Third National Health and Nutrition Examination Survey, 1988–1991. Hypertension. 1995; 25: 305–313.[Abstract/Free Full Text]

3. National High Blood Pressure Education Program Working Group Report on Hypertension in the Elderly. National High Blood Pressure Education Program Working Group. Hypertension. 1994; 23: 275–285.[Abstract/Free Full Text]

4. MacMahon S, Peto R, Cutler J, Collins R, Sorlie P, Neaton J, Abbott R, Godwin J, Dyer A, Stamler J. Blood pressure, stroke, and coronary heart disease. Part 1, Prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet. 1990; 335: 765–774.[CrossRef][Medline] [Order article via Infotrieve]

5. Klag MJ, Whelton PK, Randall BJ, Neaton JD, 2 Brancati FRL, Ford CE, Shulman NB, Stamler J. Blood pressure and end-stage renal disease in men. N Engl J Med. 1996; 334: 13–18.[Abstract/Free Full Text]

6. Psaty BM, Smith NL, Siscovick DS, Koepsell TD, Weiss NS, Heckbert SR, Lemaitre RN, Wagner EH, Furberg CD. Health outcomes associated with antihypertensive therapies used as first-line agents. A systematic review and meta-analysis. JAMA. 1997; 277: 739–745.[Abstract/Free Full Text]

7. Hansson L. The Hypertension Optimal Treatment study and the importance of lowering blood pressure. J Hypertens. 1999; 17 (suppl): S9–S13.

8. Mayer J. Nutrition and civilization. Trans NY Acad Sci. 1967; 29: 1014–1032.[Medline] [Order article via Infotrieve]

9. Dahl LK. Possible role of salt intake in the development of essential hypertension.In: Cottier P, Bock KD, eds. Essential Hypertension-an International Symposium. Berlin: Springer Verlag; 1960: 53–65.

10. Tobian L. Salt and hypertension. Lessons from animal models that relate to human hypertension. Hypertension. 1991; 17: I52–I58.[Medline] [Order article via Infotrieve]

11. Oliver WB, Cohen EL, Neel JV. Blood pressure, sodium intake, and sodium related hormones in the Yanomamo Indians, a "no-salt" culture. Circulation. 1975; 52: 146–151.[Abstract/Free Full Text]

12. Eaton SB, Konner M. Paleolithic nutrition. N Engl J Med. 1985; 312: 283–289.[Medline] [Order article via Infotrieve]

13. Guyton AC, Coleman TG, Cowley AV, Scheel KW, Manning RD Jr, Norman RA Jr. Arterial pressure regulation. Overriding dominance of the kidneys in long-term regulation and in hypertension. Am J Med. 1972; 52: 584–594.[CrossRef][Medline] [Order article via Infotrieve]

14. Mazzali M, Hughes J, Kim YG, Jefferson JA, Kang DH, Gordon KL, Lan HY, Kivlighn S, Johnson RJ. Elevated uric acid increases blood pressure in the rat by a novel crystal-independent mechanism. Hypertension. 2001; 38: 1101–1106.[Abstract/Free Full Text]

15. Mazzali M, Kanellis J, Han L, Feng L, Xia Y-Y, Chen Q, Kang D-H, Watanabe S, Nakagawa T, Lan HY, Johnson RJ. Hyperuricemia induces a primary arteriolpathy in rats by a blood pressure-independent mechanism. Am J Physiol Renal Physiol. 2002; 6: F991–F997.

16. Wu X, Muzny DM, Lee CC, Caskey CT. Two independent mutational events in the loss of urate oxidase during hominoid evolution. J Mol Evol. 1992; 34: 78–84.[CrossRef][Medline] [Order article via Infotrieve]

17. Sarich VM, Wilson AC. Generation time and genomic evolution in primates. Science. 1973; 179: 1144–1147.[Free Full Text]

18. Sibley CG, Ahlquist JE. The phylogeny of the hominoid primates, as indicated by DNA-DNA hybridization. J Mol Evol. 1984; 20: 2–15.[CrossRef][Medline] [Order article via Infotrieve]

19. Christen P, Peackock WC, Christen AE, Wacker WE. Urate oxidase in primate phylogenesis. Eur J Biochem. 1970; 12: 3–5.[Medline] [Order article via Infotrieve]

20. Goodman M. Molecular Evolution ’99. The Genomic Record of Humankind’s Evolutionary Roots. Am J Hum Genet. 1999; 64: 31–39.[CrossRef][Medline] [Order article via Infotrieve]

21. Wacker WE. Man: sapient but gouty. N Engl J Med. 1970; 283: 151–152.[Medline] [Order article via Infotrieve]

22. Andrews P. Evolution and environment in the Hominoidea. Nature. 1992; 360: 641–646.[CrossRef]

23. Pilbeam D. Genetic and morphological records of the Hominoidea and hominid origins: a synthesis. Mol Phylogenet Evol. 1996; 5: 155–168.[CrossRef][Medline] [Order article via Infotrieve]

24. Andrews P, Martin L. Hominoid dietary evolution. Philos Trans R Soc Lond B Biol Sci. 1991; 334: 199–209.[CrossRef][Medline] [Order article via Infotrieve]

25. Agusti J, Andrews P, Fortelius M, Rook L. Hominoid evolution and environmental change in the Neogene of Europe: a European Science Foundation network. J Hum Evol. 1998; 94: 103–107.

26. WoldeGabriel G, Haile-Selassie Y, Renne PR, Hart WK, Ambrose SH, Asfaw B, Heiken G, White T. Geology and palaeontology of the Late Miocene Middle Awash valley, Afar rift, Ethiopia. Nature. 2001; 412: 175–178.[CrossRef]

27. Johnson ME, Viggiano L, Bailey JA, Abdul-Rauf M, Goodwin G, Rocchi M, Eichler EE. Positive selection of a gene family during the emergence of humans and African apes. Nature. 2001; 413: 514–519.[CrossRef][Medline] [Order article via Infotrieve]

28. Gebo DL. Climbing, brachiation and terrestrial quadrupedalism: historical precursors of hominid bipedalism. Am J Phys Anthropol. 1996; 101: 55–92.[CrossRef][Medline] [Order article via Infotrieve]

29. Ames BN, Cathcart R, Schwiers EE, Hochstein P. Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis. Proc Natl Acad Sci U S A. 1981; 78: 6858–6862.[Abstract/Free Full Text]

30. Jossa F, Farinaro E, Panico S, Krogh V, Celentano E, Galasso R, Mancini M, Trevisan M. Serum uric acid and hypertension: the Olivetti heart study. J Hum Hypertens. 1994; 8: 677–681.[Medline] [Order article via Infotrieve]

31. Selby JV, Friedman GD, Quesenberry CP. Precursors of essential hypertension: pulmonary function, heart rate, uric acid, serum cholesterol, and other serum chemistries. Am J Epidemiol. 1990; 131: 1017–1027.[Abstract/Free Full Text]

32. Cannon PJ, Stason WB, Demartini FE, Sommers SC, Laragh JH. Hyperuricemia in primary and renal hypertension. N Engl J Med. 1966; 275: 457–464.[Medline] [Order article via Infotrieve]

33. Goldblatt. H. The renal origin of hypertension. Physiol Rev. 1947; 27: 120–165.[Free Full Text]

34. Johnson RJ, Herrera-Acosta J, Schreiner GF, Rodríguez-Iturbe B. Subtle acquired renal injury as a mechanism of salt-sensitive hypertension. N Engl J Med. 2002; 346: 913–923.[Free Full Text]

35. Rao GN, Corson MA, Berk BC. Uric acid stimulates vascular smooth muscle cell proliferation by increasing platelet-derived growth factor A-chain expression. J Biol Chem. 1991; 266: 8604–8608.[Abstract/Free Full Text]

36. Alderman MH, Cohen H, Madhavean S, Kivlighn S. Serum uric acid and cardiovascular events in successfully treated hypertensive patients. Hypertension. 1999; 34: 144–150.[Abstract/Free Full Text]

37. Verdecchia P, Schillaci G, Reboldi GP, Santeusanio F, Porcellati C, Brunetti P. Relation between serum uric acid and risk of cardiovascular disease in essential hypertension. The PIUMA study. Hypertension. 2000; 36: 1072–1078.[Abstract/Free Full Text]

38. Hochberg MC, Thomas J, Tomas DJ, Mead L, Levine DM, Klag MJ. Racial differences in the incidence of gout. Arthritis Rheum. 1995; 38: 628–632.[Medline] [Order article via Infotrieve]

39. Johnson RJ, Kivlighn SD, Kim Y-G, Suga S, Fogo A. Reappraisal of the pathogenesis and consequences of hyperuricemia in hypertension, cardiovascular disease, and renal disease. Am J Kid Dis. 1999; 33: 225–234.[Medline] [Order article via Infotrieve]

40. Vaccarino V, Krunholz HM. Risk factors for cardiovascular disease: one down, many more to evaluate. Ann Int Med. 1999; 131: 62–63.[Free Full Text]

41. Frohlich ED. Uric acid: a risk factor for coronary artery disease. JAMA. 1993; 270: 354–359.[Abstract/Free Full Text]

42. Ferris TF, Gorden. P Effect of angiotensin and norepinephrine upon urate clearance in man. Am J Med. 1968; 44: 359–365.[CrossRef][Medline] [Order article via Infotrieve]

This article has been cited by other articles:

				M. Shimada, R. J. Johnson, W. S. May Jr, V. Lingegowda, P. Sood, T. Nakagawa, Q. C. Van, B. Dass, and A. A. Ejaz A novel role for uric acid in acute kidney injury associated with tumour lysis syndrome Nephrol. Dial. Transplant., July 6, 2009; (2009) gfp330v1. [Full Text] [PDF]

				R. J. Johnson, S. E. Perez-Pozo, Y. Y. Sautin, J. Manitius, L. G. Sanchez-Lozada, D. I. Feig, M. Shafiu, M. Segal, R. J. Glassock, M. Shimada, et al. Hypothesis: Could Excessive Fructose Intake and Uric Acid Cause Type 2 Diabetes? Endocr. Rev., February 1, 2009; 30(1): 96 - 116. [Abstract] [Full Text] [PDF]

				M. K. Leow, C. Bueno, N. Trivedi, M. S. Parmar, J. Oh, H. Y. Won, S.-M. Kang, L. A. Hebert, B. Rovin, D. I. Feig, et al. Uric Acid and Cardiovascular Risk N. Engl. J. Med., January 29, 2009; 360(5): 538 - 541. [Full Text] [PDF]

				D. I. Feig, D.-H. Kang, and R. J. Johnson Uric Acid and Cardiovascular Risk N. Engl. J. Med., October 23, 2008; 359(17): 1811 - 1821. [Full Text] [PDF]

				D. I. Feig, B. Soletsky, and R. J. Johnson Effect of Allopurinol on Blood Pressure of Adolescents With Newly Diagnosed Essential Hypertension: A Randomized Trial JAMA, August 27, 2008; 300(8): 924 - 932. [Abstract] [Full Text] [PDF]

				J. M. Hare, B. Mangal, J. Brown, C. Fisher Jr, R. Freudenberger, W. S. Colucci, D. L. Mann, P. Liu, M. M. Givertz, R. P. Schwarz, et al. Impact of oxypurinol in patients with symptomatic heart failure. Results of the OPT-CHF study. J. Am. Coll. Cardiol., June 17, 2008; 51(24): 2301 - 2309. [Abstract] [Full Text] [PDF]

				C. Meisinger, W. Koenig, J. Baumert, and A. Doring Uric Acid Levels Are Associated With All-Cause and Cardiovascular Disease Mortality Independent of Systemic Inflammation in Men From the General Population: The MONICA/KORA Cohort Study Arterioscler. Thromb. Vasc. Biol., June 1, 2008; 28(6): 1186 - 1192. [Abstract] [Full Text] [PDF]

				A. Boueiz, M. Damarla, and P. M. Hassoun Xanthine oxidoreductase in respiratory and cardiovascular disorders Am J Physiol Lung Cell Mol Physiol, May 1, 2008; 294(5): L830 - L840. [Abstract] [Full Text] [PDF]

				S. A. Eraly, V. Vallon, T. Rieg, J. A. Gangoiti, W. R. Wikoff, G. Siuzdak, B. A. Barshop, and S. K. Nigam Multiple organic anion transporters contribute to net renal excretion of uric acid Physiol Genomics, April 1, 2008; 33(2): 180 - 192. [Abstract] [Full Text] [PDF]

				M. K. Kutzing and B. L. Firestein Altered Uric Acid Levels and Disease States J. Pharmacol. Exp. Ther., January 1, 2008; 324(1): 1 - 7. [Abstract] [Full Text] [PDF]

				R. J Johnson, M. S Segal, Y. Sautin, T. Nakagawa, D. I Feig, D.-H. Kang, M. S Gersch, S. Benner, and L. G Sanchez-Lozada Potential role of sugar (fructose) in the epidemic of hypertension, obesity and the metabolic syndrome, diabetes, kidney disease, and cardiovascular disease Am. J. Clinical Nutrition, October 1, 2007; 86(4): 899 - 906. [Abstract] [Full Text] [PDF]

				C. Roncal, W. Mu, S. Reungjui, K. M. Kim, G. N. Henderson, X. Ouyang, T. Nakagawa, and R. J. Johnson Lead, at low levels, accelerates arteriolopathy and tubulointerstitial injury in chronic kidney disease Am J Physiol Renal Physiol, October 1, 2007; 293(4): F1391 - F1396. [Abstract] [Full Text] [PDF]

				Y. Y. Sautin, T. Nakagawa, S. Zharikov, and R. J. Johnson Adverse effects of the classic antioxidant uric acid in adipocytes: NADPH oxidase-mediated oxidative/nitrosative stress Am J Physiol Cell Physiol, August 1, 2007; 293(2): C584 - C596. [Abstract] [Full Text] [PDF]

				P. B. Mellen, A. J. Bleyer, and D. M. Herrington Response to Treatment of Hyperuricemia in Essential Hypertension Hypertension, June 1, 2007; 49(6): e46 - e46. [Full Text] [PDF]

				D. Patschan, S. Patschan, G. G. Gobe, S. Chintala, and M. S. Goligorsky Uric Acid Heralds Ischemic Tissue Injury to Mobilize Endothelial Progenitor Cells J. Am. Soc. Nephrol., May 1, 2007; 18(5): 1516 - 1524. [Abstract] [Full Text] [PDF]

				L. G. Sanchez-Lozada, E. Tapia, R. Lopez-Molina, T. Nepomuceno, V. Soto, C. Avila-Casado, T. Nakagawa, R. J. Johnson, J. Herrera-Acosta, and M. Franco Effects of acute and chronic L-arginine treatment in experimental hyperuricemia Am J Physiol Renal Physiol, April 1, 2007; 292(4): F1238 - F1244. [Abstract] [Full Text] [PDF]

				Y. Hagos, D. Stein, B. Ugele, G. Burckhardt, and A. Bahn Human Renal Organic Anion Transporter 4 Operates as an Asymmetric Urate Transporter J. Am. Soc. Nephrol., February 1, 2007; 18(2): 430 - 439. [Abstract] [Full Text] [PDF]

				A. B. Weder Evolution and Hypertension Hypertension, February 1, 2007; 49(2): 260 - 265. [Full Text] [PDF]

				C. A. Roncal, W. Mu, B. Croker, S. Reungjui, X. Ouyang, I. Tabah-Fisch, R. J. Johnson, and A. Ahsan Ejaz Effect of elevated serum uric acid on cisplatin-induced acute renal failure Am J Physiol Renal Physiol, January 1, 2007; 292(1): F116 - F122. [Abstract] [Full Text] [PDF]

				J. P. Forman, H. Choi, and G. C. Curhan Plasma Uric Acid Level and Risk for Incident Hypertension Among Men J. Am. Soc. Nephrol., January 1, 2007; 18(1): 287 - 292. [Abstract] [Full Text] [PDF]

				H. J. Han, M. J. Lim, Y. J. Lee, J. H. Lee, I. S. Yang, and M. Taub Uric acid inhibits renal proximal tubule cell proliferation via at least two signaling pathways involving PKC, MAPK, cPLA2, and NF-{kappa}B Am J Physiol Renal Physiol, January 1, 2007; 292(1): F373 - F381. [Abstract] [Full Text] [PDF]

				M. J. Bos, P. J. Koudstaal, A. Hofman, J. C.M. Witteman, and M. M.B. Breteler Uric Acid Is a Risk Factor for Myocardial Infarction and Stroke: The Rotterdam Study Stroke, June 1, 2006; 37(6): 1503 - 1507. [Abstract] [Full Text] [PDF]

				C. Ruggiero, A. Cherubini, A. Ble, A. J.G. Bos, M. Maggio, V. D. Dixit, F. Lauretani, S. Bandinelli, U. Senin, and L. Ferrucci Uric acid and inflammatory markers Eur. Heart J., May 2, 2006; 27(10): 1174 - 1181. [Abstract] [Full Text] [PDF]

				D. I. Feig, M. Mazzali, D.-H. Kang, T. Nakagawa, K. Price, J. Kannelis, and R. J. Johnson Serum Uric Acid: A Risk Factor and a Target for Treatment? J. Am. Soc. Nephrol., April 1, 2006; 17(4_suppl_2): S69 - S73. [Abstract] [Full Text] [PDF]

				Y. Iwashima, T. Horio, K. Kamide, H. Rakugi, T. Ogihara, and Y. Kawano Uric Acid, Left Ventricular Mass Index, and Risk of Cardiovascular Disease in Essential Hypertension Hypertension, February 1, 2006; 47(2): 195 - 202. [Abstract] [Full Text] [PDF]

				D.-H. Kang, S.-K. Park, I.-K. Lee, and R. J. Johnson Uric Acid-Induced C-Reactive Protein Expression: Implication on Cell Proliferation and Nitric Oxide Production of Human Vascular Cells J. Am. Soc. Nephrol., December 1, 2005; 16(12): 3553 - 3562. [Abstract] [Full Text] [PDF]

				J. M. Roberts, L. M. Bodnar, K. Y. Lain, C. A. Hubel, N. Markovic, R. B. Ness, and R. W. Powers Uric Acid Is as Important as Proteinuria in Identifying Fetal Risk in Women With Gestational Hypertension Hypertension, December 1, 2005; 46(6): 1263 - 1269. [Abstract] [Full Text] [PDF]

				H. K. Choi, D. B. Mount, and A. M. Reginato Pathogenesis of Gout Ann Intern Med, October 4, 2005; 143(7): 499 - 516. [Full Text] [PDF]

				R. J. Johnson, M. S. Segal, T. Srinivas, A. Ejaz, W. Mu, C. Roncal, L. G. Sanchez-Lozada, M. Gersch, B. Rodriguez-Iturbe, D.-H. Kang, et al. Essential Hypertension, Progressive Renal Disease, and Uric Acid: A Pathogenetic Link? J. Am. Soc. Nephrol., July 1, 2005; 16(7): 1909 - 1919. [Abstract] [Full Text] [PDF]

				M. A. Hediger, R. J Johnson, H. Miyazaki, and H. Endou Molecular Physiology of Urate Transport Physiology, April 1, 2005; 20(2): 125 - 133. [Abstract] [Full Text] [PDF]

				R. J. Johnson, B. Rodriguez-Iturbe, T. Nakagawa, D.-H. Kang, D. I. Feig, and J. Herrera-Acosta Subtle Renal Injury Is Likely a Common Mechanism for Salt-Sensitive Essential Hypertension Hypertension, March 1, 2005; 45(3): 326 - 330. [Full Text] [PDF]

				K.S. Kamel, S. Cheema-Dhadli, M.A. Shafiee, M.R. Davids, and M.L. Halperin Recurrent uric acid stones QJM, January 1, 2005; 98(1): 57 - 68. [Abstract] [Full Text] [PDF]

				R. J. Johnson, D. I. Feig, J. Herrera-Acosta, and D.-H. Kang Resurrection of Uric Acid as a Causal Risk Factor in Essential Hypertension Hypertension, January 1, 2005; 45(1): 18 - 20. [Full Text] [PDF]

				A. B. Alper Jr, W. Chen, L. Yau, S. R. Srinivasan, G. S. Berenson, and L. L. Hamm Childhood Uric Acid Predicts Adult Blood Pressure: The Bogalusa Heart Study Hypertension, January 1, 2005; 45(1): 34 - 38. [Abstract] [Full Text] [PDF]

				T. Ohtsubo, I. I. Rovira, M. F. Starost, C. Liu, and T. Finkel Xanthine Oxidoreductase Is an Endogenous Regulator of Cyclooxygenase-2 Circ. Res., November 26, 2004; 95(11): 1118 - 1124. [Abstract] [Full Text] [PDF]

				C. E. Berry and J. M. Hare Xanthine oxidoreductase and cardiovascular disease: molecular mechanisms and pathophysiological implications J. Physiol., March 15, 2004; 555(3): 589 - 606. [Abstract] [Full Text] [PDF]

				W. A. Wilmer, B. H. Rovin, C. J. Hebert, S. V. Rao, K. Kumor, and L. A. Hebert Management of Glomerular Proteinuria: A Commentary J. Am. Soc. Nephrol., December 1, 2003; 14(12): 3217 - 3232. [Abstract] [Full Text] [PDF]

				K. Masuo, H. Kawaguchi, H. Mikami, T. Ogihara, and M. L. Tuck Serum Uric Acid and Plasma Norepinephrine Concentrations Predict Subsequent Weight Gain and Blood Pressure Elevation Hypertension, October 1, 2003; 42(4): 474 - 480. [Abstract] [Full Text] [PDF]

				D. I. Feig and R. J. Johnson Hyperuricemia in Childhood Primary Hypertension Hypertension, September 1, 2003; 42(3): 247 - 252. [Abstract] [Full Text] [PDF]

				J. Kanellis and R. J. Johnson Editorial Comment--Elevated Uric Acid and Ischemic Stroke: Accumulating Evidence That It Is Injurious and Not Neuroprotective Stroke, August 1, 2003; 34(8): 1956 - 1957. [Full Text] [PDF]

				R. J. Johnson, D.-H. Kang, D. Feig, S. Kivlighn, J. Kanellis, S. Watanabe, K. R. Tuttle, B. Rodriguez-Iturbe, J. Herrera-Acosta, and M. Mazzali Is There a Pathogenetic Role for Uric Acid in Hypertension and Cardiovascular and Renal Disease? Hypertension, June 1, 2003; 41(6): 1183 - 1190. [Abstract] [Full Text] [PDF]

				J. Kanellis, S. Watanabe, J. H. Li, D. H. Kang, P. Li, T. Nakagawa, A. Wamsley, D. Sheikh-Hamad, H. Y. Lan, L. Feng, et al. Uric Acid Stimulates Monocyte Chemoattractant Protein-1 Production in Vascular Smooth Muscle Cells Via Mitogen-Activated Protein Kinase and Cyclooxygenase-2 Hypertension, June 1, 2003; 41(6): 1287 - 1293. [Abstract] [Full Text] [PDF]

				J. M. Hare and R. J. Johnson Uric Acid Predicts Clinical Outcomes in Heart Failure: Insights Regarding the Role of Xanthine Oxidase and Uric Acid in Disease Pathophysiology Circulation, April 22, 2003; 107(15): 1951 - 1953. [Full Text] [PDF]

This Article Abstract Full Text (PDF) All Versions of this Article: 40/3/355    most recent 01.HYP.0000028589.66335.AAv1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Watanabe, S. Articles by Johnson, R. J. Search for Related Content PubMed PubMed Citation Articles by Watanabe, S. Articles by Johnson, R. J. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Dietary Sodium Related Collections Genetics of cardiovascular disease