![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
PERSPECTIVES IN PHARMACOLOGY
Department of Cell Biology and Neuroscience (M.K.K., B.L.F.), Graduate Program in Biomedical Engineering (M.K.K.), Rutgers University, Piscataway, New Jersey
Received July 23, 2007; accepted September 20, 2007.
 |
Abstract |
|---|
; Choi et al., 2005).
|
Alternatively, increasing UA levels has been proposed as a therapy for the treatment of neurodegenerative diseases, such as multiple sclerosis (MS), and for the treatment of both spinal cord injury and stroke because of the neuroprotective properties of UA. UA has been found to both prevent and alleviate the symptoms of experimental allergic encephalomyelitis (EAE), the animal model of MS, in mice (Hooper et al., 2000). The administration of inosine, a UA precursor, has been shown to have a similar therapeutic effect in the treatment of EAE (Scott et al., 2002). Some success was reported using inosine to treat MS patients as a method of raising the serum UA concentration (Spitsin et al., 2001a). Likewise, both UA and inosine have recently been implicated as possible treatments following spinal cord injury. Our laboratory has recently reported that the administration of UA after a simulated spinal cord injury in vitro resulted in a decrease in secondary neuronal damage (Du et al., 2007). This result is in agreement with in vivo studies by Hooper and colleagues that showed that UA protects when administered before spinal cord injury (Scott et al., 2005). A related result by Ju and colleagues found that inosine also protects spinal cord neurons from secondary damage (Liu et al., 2006).
The adjustment of UA levels as a treatment strategy has proven to be successful for a number of disorders; however, because disease states result from both high and low UA levels, the manipulation of UA levels above or below normal levels could possibly lead to unwanted side effects. Ideally, decreasing UA levels to treat a disease caused by an elevated UA level should not leave a patient more susceptible to the development of a condition that may result from a reduced UA level. This review will outline the variety of disease states that have been shown to, or are believed to, result from altered serum UA levels. It will also briefly summarize some of the mechanisms by which altered UA levels can lead to such conditions.
|
Uric Acid Balance |
|---|
). A number of kidney urate transporters are involved in the regulation of plasma urate levels. These include urate transporter 1 (URAT1), which is responsible for the reabsorption of urate. Also included are a number of organic ion transporters (OAT), such as OAT1 and OAT3, and ATP-dependent urate export transporter MRP4, all of which are probably involved in urate secretion. In humans, approximately 90% of the filtered urate is reabsorbed. Thus, because of its involvement in urate reabsorption, URAT1 is believed to be critical in the regulation of plasma urate levels (Hediger et al., 2005; Anzai et al., 2007).
UA is produced from purines by the enzyme xanthine oxidase via the purine metabolism pathway (Fig. 1) (Waring et al., 2000a). In the majority of mammals, UA is further degraded to allantoin via the urate oxidase (uricase) enzyme. Allantoin is then freely excreted from the body in the urine (Waring et al., 2000a). However, during the Miocene epoch, two separate mutations occurred that resulted in a nonfunctioning uricase gene. Consequently, humans, apes, and certain New World monkeys have higher UA levels (>2 mg/dl or 120 µM) compared with other mammals (<2 mg/dl) (Johnson et al., 2003).
|
A range of serum UA concentrations has been defined for both hyperuricemia and hypouricemia. Hyperuricemia has been defined for men as a UA concentration greater than 386 µM in one study (Klemp et al., 1997) and greater than 420 µM in a separate study (Johnson et al., 2003). For women, most studies define hyperuricemia as a concentration greater than approximately 360 µM (Klemp et al., 1997; Johnson et al., 2003). Hypouricemia is generally defined as a UA concentration of less than approximately 120 µM (Hisatome et al., 1996). Thus, the normal range of UA concentration falls somewhere between 120 and 380 µM, varying slightly depending on gender.
|
Elevated Uric Acid Levels |
|---|
; Choi et al., 2005). Hyperuricemia has been shown to be linked to a number of diseases and conditions, including gout, hypertension, cardiovascular disease, myocardial infarction, stroke, and renal disease (Jossa et al., 1994; Freedman et al., 1995; Kang et al., 2002; Choi et al., 2005; Bos et al., 2006). However, it remains unclear whether an increased UA level is the cause or a consequence of some of these conditions. |
Hyperuricemia, Gout, and Kidney Disease |
|---|
; Choi et al., 2005), an inflammatory arthritis that results from the crystallization of UA within the joints (Choi et al., 2005). A direct positive association between serum urate levels and a future risk for gout has been reported. Specifically, as urate concentration increases, the risk for crystal formation increases, raising a patient's susceptibility to the development of gout (Lin et al., 2000). Approximately 20 to 60% of patients with gout also have mild or moderate renal dysfunction, indicating a possible link between an elevated UA level and renal disease (Berger and Yu, 1975). Although hyperuricemia may simply be a marker of renal disease, there are some studies that suggest that elevated UA levels might contribute to the development and progression of renal dysfunction (Saito et al., 1978; Kang et al., 2002). An epidemiological study of patients with normal renal function found that a serum UA concentration of >8.0 mg/dl, compared with a serum UA concentration of <5.0 mg/dl, is associated with a 2.9 times increased risk of the development of renal deficiency in men and a 10 times increased risk in women within 2 years (Saito et al., 1978). Furthermore, a study that induced hyperuricemia in rats with the remnant kidney model of progressive kidney disease found that a mild elevation in serum UA concentration led to a significant increase in the progression of renal disease. Specifically, an increase in a number of conditions associated with renal disease was reported, including renal hypertrophy, hypertension, proteinuria (an excess of protein in the urine), glomerulosclerosis, and interstitial fibrosis. A possible mechanism by which UA may worsen the progression of kidney disease is by the activation of the renin angiotensin system (RAS). The RAS has been identified as a contributor to the progression of renal disease by increasing both systemic and glomerular pressure and by directly causing the fibrosis of renal and vascular cells (Kang et al., 2002). A recent study that indirectly quantified RAS activation through the measurement of renal vasoconstriction in response to the administration of angiotensin II found that renovascular responsiveness to angiotensin II and thus RAS activation is independently associated with plasma UA concentration. However, whereas this association is now fairly well established, the underlying mechanism through which an elevated UA concentration stimulates RAS remains unclear (Perlstein et al., 2004). |
Hyperuricemia and Hypertension |
|---|
). The elevated UA level may be caused by the decrease in renal blood flow that develops in the early stages of hypertension. A reduced renal blood flow could alter the balance between medullary and cortical circulation, possibly resulting in a decrease in urate secretion. This could ultimately lead to an overall increase in the serum UA level (Messerli et al., 1980). Hypertension can also lead to microvascular disease that can cause local tissue ischemia (Puig and Ruilope, 1999). Tissue ischemia can then lead to an increase in the synthesis of UA, ultimately resulting in an increased serum UA level (Friedl et al., 1991). These mechanisms indicate that the increase in the plasma UA level may be a consequence rather than a cause of hypertension. |
Hyperuricemia and Cardiovascular Disease |
|---|
), myocardial infarction, and stroke (Bos et al., 2006). Bos et al. (2006) found a significant positive association between serum UA levels and the risk of both heart disease and stroke. Elevated UA levels were also found to be an independent risk factor for overall cardiovascular mortality (Fang and Alderman, 2000). Furthermore, serum UA levels were found to be significantly higher in patients with established coronary heart disease compared with healthy patients (Torun et al., 1998). The association of high serum UA levels with cardiovascular disease may be due to the role of uric acid as an antioxidant (Ames et al., 1981; Davies et al., 1986), because an elevated serum UA level may be a defense mechanism against atherosclerosis. UA concentrations may increase in an attempt to block lipid peroxidation and other related phenomena (Nieto et al., 2000). This again suggests that elevated UA levels are a consequence of disease. On the other hand, increased UA levels may instead contribute to the development of cardiovascular disease by exerting a negative effect on the endothelium. There is some evidence that serum UA could possibly promote, rather than prevent, oxygenation of low-density lipoprotein cholesterol and lipid peroxidation (De Scheerder et al., 1991). This can lead to an increase in platelet adhesiveness, resulting in thrombus formation that can contribute to the development of atherosclerosis, increasing the likelihood of the development of cardiovascular disease. High UA levels can also stimulate the release of free radicals, which have been shown to be involved in adhesion molecule expression by inflammatory cells as well as in inflammatory cell activation and adherence to the damaged endothelium (Waring et al., 2000a). This ultimately results in endothelial injury, again increasing the risk of cardiovascular disease development. This mechanism is supported by the positive correlation found between elevated UA levels and chronic inflammation in chronic heart failure (Leyva et al., 1998). In addition, an elevation in plasma UA concentration is associated with an increased level of C-reactive protein that has been identified as an important indicator of myocardial infarction, stroke, and vascular death (Kang et al., 2005). |
Elevated Serum Uric Acid Concentration: Cause or Consequence of Disease? |
|---|
), or hyperlipidemia (Puig et al., 1991). However, numerous other studies found UA concentration to be an independent risk factor of disease development, even after adjusting for these other factors (Jossa et al., 1994; Bos et al., 2006). Thus, there remains a strong possibility that UA could play a pathogenic role in hypertension, cardiovascular disease, and renal disease. In addition, recent studies have found that an elevated serum UA concentration as a child is associated with an increased blood pressure as an adult and is likely to contribute to the development of early onset essential hypertension (Alper et al., 2005).
Numerous studies have investigated the effects of directly increasing plasma UA levels. These findings provide added support that elevated UA levels are at least partly responsible for the development of a number of disease states. Maxwell and colleagues found that increasing UA levels in healthy humans resulted in impaired acetylcholine-induced vasodilation in the forearm (Waring et al., 2000b). This suggests an alteration in the release of nitric oxide, as nitric oxide is an important mediator of arterial vasodilation as a means of increasing blood flow. Furthermore, increasing serum UA levels in animal models has been shown to inhibit the nitric oxide system in the kidney (Johnson et al., 2003). In other studies, mild hyperuricemic rats developed hypertension and an increase in blood pressure after several weeks (Mazzali et al., 2001; Sanchez-Lozada et al., 2002). In these studies, the hypertension and blood pressure increase could be prevented by maintaining UA levels in the normal range with the administration of allopurinol (Mazzali et al., 2001). Animal models of chronically hyperuricemic rats have resulted in a persistent afferent arteriolopathy resulting in an increased media/lumen ratio (Watanabe et al., 2002). Finally, renal injury was also reported in hyperuricemic rats, and these changes could again be prevented by maintaining serum uric acid levels in the normal range (Sanchez-Lozada et al., 2002).
|
Methods for Reducing Serum Uric Acid Levels |
|---|
; Choi et al., 2005). |
Reduced Uric Acid Levels |
|---|
; Toncev et al., 2002; Knapp et al., 2004; de Lau et al., 2005; Kim et al., 2006). In these inflammatory diseases, a decreased UA concentration may not be able to prevent the toxicity by reactive oxygen and nitrogen species that form as a result of the inflammation. Peroxynitrite, in particular, is believed to have a significant negative impact on cellular function and survival (Pacher et al., 2007). |
The Role of Peroxynitrite in Inflammation |
|---|
) whenever the two are within a few cell diameters of one another. The reaction is diffusion-limited due to the ability of nitric oxide to move between cells and through cell membranes. Thus, the production of NO and superoxide does not necessarily have to occur within the same area or even within the same cell for a reaction to occur and result in the formation of peroxynitrite (Pacher et al., 2007). Individually, neither NO nor superoxide is especially toxic in vivo. Superoxide is quickly removed by the scavenging enzyme superoxide dismutase, and NO is removed by rapid diffusion into the red blood cells where it is converted via a reaction with oxyhemoglobin to nitrite. Because of the high concentration of NO that is produced in vivo, along with the rapid reaction rate of NO with superoxide, NO is able to outcompete superoxide dismutase for reaction with superoxide whenever both species are present (Beckman, 1996).
Peroxynitrite is a strong oxidant that can react directly with electron-rich groups of a number of biological molecules, leading to oxidative damage. It reacts relatively slowly with most biological molecules because of its unusual stability. As a result, peroxynitrite is able to collide with billions of biological molecules without undergoing a reaction, allowing it to be selective in the biological molecules with which it reacts (Beckman, 1996). Under normal physiological conditions, there is a low production of peroxynitrite, resulting in a minimal amount of oxidative damage. However, a small increase in NO and superoxide formation produces a much larger increase in peroxynitrite formation. Even a slight increase in peroxynitrite production can result in substantial oxidation that can lead to tissue destruction and can damage a number of processes that are critical for normal cellular function (Pacher et al., 2007). Peroxynitrite toxicity results from a number of different mechanisms, including the nitration of amino acids, such as tyrosine and cysteine (Ischiropoulos et al., 1992), and DNA mutations and breakages resulting from oxidation modifications that ultimately lead to cell death via necrosis or apoptosis (Inoue and Kawanishi, 1995). Tyrosine nitration can lead to the alteration and inactivation of a number of enzymes and to modifications in the cytoskeletal organization. Structural proteins have an abundance of tyrosine residues, making them an attractive target for nitration. The nitration of structural proteins can have significant consequences because the alteration of one subunit can result in the improper formation of the entire structure (Pacher et al., 2007). Peroxynitrite can also inhibit the mitochondrial electron transport chain (Radi et al., 1994) by altering the permeability of the mitochondrial outer membrane (Pacher et al., 2007). This can result in a state of cellular energy deficiency and can damage a number of cellular components, including lipids, proteins, and nucleic acids, again resulting in cell death (Smith et al., 1999). Peroxynitrite can also activate cell death by altering essential signal transduction pathways (Pacher et al., 2007).
|
Peroxynitrite and Disease |
|---|
). The inflammation that occurs in neurodegenerative diseases directly encourages the production of NO and superoxide, leading to a vast increase in peroxynitrite formation (Radi et al., 1991). A number of studies have documented the involvement of peroxynitrite and other reactive nitrogen species in MS. Nitrotyrosine has been identified in the cells surrounding the plaque areas of postmortem brains of MS patients (Spitsin et al., 2001b). An increase in the levels of inducible nitric-oxide synthase, an enzyme involved in the production of NO, has also been found in the macrophages, microglia, and astrocytes of demyelinating plaques of MS patients (Bagasra et al., 1995). Furthermore, elevated NO concentrations were measured in mice with EAE (Hooper et al., 1995). Evidence of oxidative stress was also identified in post-mortem studies of patients with PD (Jenner, 2003). Specifically, an increased accumulation of nitrotyrosine was found in both Lewy bodies, a structure often found in the brains of Parkinson's patients, as well as in polymorphonuclear cells (Gatto et al., 2000).
Peroxynitrite, along with other free radicals, is believed to be involved in the inflammation, demyelination, and axonal injury that occur during MS (Toncev et al., 2002). Free radical production can increase inflammation and lead to tissue damage. Peroxynitrite is thought to play a role in the demyelination that occurs during MS because of its ability to induce lipid peroxidation of the highly fatty myelin sheath that surrounds the oligodendrocytes (van der Veen et al., 1997). Pathological studies have shown that axonal damage in MS is most prevalent in regions with increased inflammation and demyelination, suggesting that axonal damage is also a result of the actions of free radicals and cytokines (Ferguson et al., 1997). Oxidative stress resulting from an excess of free radicals is also implicated in the pathogenesis of AD (Jenner, 2003). An increased neuronal nitric-oxide synthase expression has been reported in both neurons with neurofibrillary tangles in the hippocampus and cortex and in reactive astrocytes close to amyloid plaques in AD patients, suggesting that both neurons and astrocytes are affected by peroxynitrite (Thorns et al., 1998; Simic et al., 2000). In PD, oxidative damage to lipids, proteins, and DNA has been identified (Gatto et al., 2000; Jenner, 2003). In addition, toxic products of oxidative damage, such as 4-hydroxynonenal, have been shown to impair cell viability in patients with PD through their reaction with various proteins (Jenner, 2003).
|
Uric Acid and Neuroprotection |
|---|
). UA can scavenge superoxide, the hydroxyl radical, and singlet oxygen (Ames et al., 1981; Davies et al., 1986). UA may assist in the removal of superoxide by preventing against the degradation of superoxide dismutase, the enzyme that is responsible for clearing superoxide from the cell (Pacher et al., 2007). Removal of superoxide helps to prevent its reaction with NO, blocking the formation of peroxynitrite (van der Veen et al., 1997). UA is also very effective at preventing peroxynitrite from nitrating the tyrosine residues of proteins, thereby preventing the inactivation of cellular enzymes and modification of the cytoskeleton (i.e., Pacher et al., 2007). UA also has the ability to bind iron and inhibit iron-dependent ascorbate oxidation, preventing an increased production of free radicals that can further contribute to oxidative damage (Davies et al., 1986). Thus, a reduced UA concentration may decrease the ability of the body to prevent peroxynitrite and other free radicals from acting on cellular components and damaging the cell. However, there are some recent studies that suggest that this may not be UA's sole method of neuroprotection. Interestingly, Squadrito et al. (2000) found that, at normal human levels, peroxynitrite binds with carbon dioxide 920 times faster than it does with UA, questioning whether UA plays a significant role in the reduction of peroxynitrite toxicity in vivo (as discussed in Du et al., 2007). Furthermore, our laboratory recently found that astroglia must be present for UA to protect spinal cord neurons in a cell culture model of spinal cord injury (Du et al., 2007). UA acts upon astroglia and up-regulates protein levels of EAAT-1, a glutamate transporter, to protect spinal cord neurons from glutamate-induced toxicity. When astroglia are not present, UA can no longer protect neurons, suggesting that UA does not act passively by merely binding reactive oxygen species. Thus, UA acts to protect cells through a more direct, astroglia-mediated mechanism (Du et al., 2007). |
Reduced Serum Uric Acid Concentration and Disease |
|---|
; Toncev et al., 2002; Rentzos et al., 2006). In epidemiological studies, both Toncev et al. (2002) and Rentzos et al. (2006) found that patients with MS have significantly lower serum UA levels compared with healthy subjects. Studies that measured UA levels in sets of monozygotic and dizygotic twins in which one of the twins has MS also found a significantly lower UA level in the siblings with MS (Spitsin et al., 2001b). There are also some studies that have found a correlation between serum UA levels and disease activity as well as between serum UA levels and BBB dysfunction. MS patients with BBB disruption were found to have significantly lower UA levels than those with no disruption. In addition, MS patients with relapse had significantly lower UA levels than those in remission (Toncev et al., 2002). A correlation was also found between UA levels and optic neuritis, an inflammatory demyelinating disease of the optic nerve that is often the first symptom of MS. Persons with optic neuritis were found to have lower serum UA levels than age- and sex-matched controls (Knapp et al., 2004). Likewise, associations between serum UA levels and the risk of disease were also reported in both AD and PD. A significant reduction in serum UA concentration was found in AD patients compared with healthy controls (Kim et al., 2006). In PD, higher serum UA levels correlated with a significant decrease in the risk of disease (de Lau et al., 2005). Furthermore, diminished levels of UA were found in the substantia nigra of PD patients (Church and Ward, 1994). Lastly, there is some recent evidence that suggests that a reduced UA concentration in the saliva may contribute to the development of tumors in the upper part of the stomach. UA is believed to be involved in defending against the nitrogen species that are generated from the reaction of salivary nitrite with acidic gastric juices. Saliva that is deficient in antioxidants, such as urate and ascorbic acid, may not be able to prevent against the potentially harmful reactive nitrogen species that can promote tissue damage and mutagenesis (Pietraforte et al., 2006). |
Reduced Serum Uric Acid Concentration: Cause or Consequence of Disease? |
|---|
). The results of the direct administration of UA and subsequent increase in serum UA concentration in mice with an acute aggressive form of EAE provide support that low UA levels are a cause, and not a consequence, of disease. Hooper et al. (1998) found that the administration of UA, when given either before or after the symptoms of EAE had appeared, promoted long-term survival of mice with EAE. Specifically, the treatment prevented against the invasion of inflammatory cells into the central nervous system by maintaining the integrity of the BBB (Kean et al., 2000). Furthermore, a recent clinical study found that the administration of inosine, a UA precursor, stopped the progression of MS in all 11 patients that received the drug and improved some of the symptoms of the disease in three of the patients (Spitsin et al., 2001a). In PD animal models, the administration of UA was found to diminish oxidative stress and prevent against cell death (Duan et al., 2002). In addition, an evaluation of epidemiological studies found that MS and gout were virtually mutually exclusive, as there were no reported cases of a patient with both MS and gout, suggesting that the increased serum UA level associated with gout can protect against MS. This again implies that low UA levels have a causal role in MS (Hooper et al., 1998). |
Conclusions |
|---|
|
Footnotes |
|---|
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: UA, uric acid; MS, multiple sclerosis; EAE, experimental allergic encephalomyelitis; NO, nitric oxide; NOS, NO synthase; PD, Parkinson's disease; AD, Alzheimer's disease; URAT1, urate transporter 1; RAS, renin angiotensin system; MRP4, multidrug resistance protein 4; OAT, organic ion transporter; BBB, blood-brain barrier.
Address correspondence to: Dr. Bonnie L. Firestein, Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854-8082. E-mail: firestein{at}biology.rutgers.edu
|
References |
|---|
Alper AB, Jr, Chen W, Yau L, Srinivasan SR, Berenson GS, and Hamm LL (2005) Childhood uric acid predicts adult blood pressure: the Bogalusa Heart Study. Hypertension 45: 34–38.
Ames BN, Cathcart R, Schwiers E, and Hochstein P (1981) 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 78: 6858–6862.
Anzai N, Kanai Y, and Endou H (2007) New insights into renal transport of urate. Curr Opin Rheumatol 19: 151–157.[Medline]
Bagasra O, Michaels FH, Zheng YM, Bobroski LE, Spitsin SV, Fu ZF, Tawadros R, and Koprowski H (1995) Activation of the inducible form of nitric oxide synthase in the brains of patients with multiple sclerosis. Proc Natl Acad Sci U S A 92: 12041–12045.
Beckman JS (1996) Oxidative damage and tyrosine nitration from peroxynitrite. Chem Res Toxicol 9: 836–844.[CrossRef][Medline]
Berger L and Yu TF (1975) Renal function in gout. IV. An analysis of 524 gouty subjects including long-term follow-up studies. Am J Med 59: 605–613.[CrossRef][Medline]
Bos MJ, Koudstaal PJ, Hofman A, Witteman JC, and Breteler MM (2006) Uric acid is a risk factor for myocardial infarction and stroke: the Rotterdam study. Stroke 37: 1503–1507.
Choi HK, Mount DB, and Reginato AM (2005) Pathogenesis of gout. Ann Intern Med 143: 499–516.
Church WH and Ward VL (1994) Uric acid is reduced in the substantia nigra in Parkinson's disease: effect on dopamine oxidation. Brain Res Bull 33: 419–425.[CrossRef][Medline]
Davies KJ, Sevanian A, Muakkassah-Kelly SF, and Hochstein P (1986) Uric acid-iron ion complexes. A new aspect of the antioxidant functions of uric acid. Biochem J 235: 747–754.[Medline]
de Lau LM, Koudstaal PJ, Hofman A, and Breteler MM (2005) Serum uric acid levels and the risk of Parkinson disease. Ann Neurol 58: 797–800.[CrossRef][Medline]
De Scheerder IK, van de Kraay AM, Lamers JM, Koster JF, de Jong JW, and Serruys PW (1991) Myocardial malondialdehyde and uric acid release after short-lasting coronary occlusions during coronary angioplasty: potential mechanisms for free radical generation. Am J Cardiol 68: 392–395.[CrossRef][Medline]
Drulovic J, Dujmovic I, Stojsavljevic N, Mesaros S, Andjelkovic S, Miljkovic D, Peric V, Dragutinovic G, Marinkovic J, Levic Z, et al. (2001) Uric acid levels in sera from patients with multiple sclerosis. J Neurol 248: 121–126.[CrossRef][Medline]
Du Y, Chen CP, Tseng CY, Eisenberg Y, and Firestein BL (2007) Astroglia-mediated effects of uric acid to protect spinal cord neurons from glutamate toxicity. Glia 55: 463–472.[CrossRef][Medline]
Duan W, Ladenheim B, Cutler RG, Kruman II, Cadet JL, and Mattson MP (2002) Dietary folate deficiency and elevated homocysteine levels endanger dopaminergic neurons in models of Parkinson's disease. J Neurochem 80: 101–110.[CrossRef][Medline]
Emmerson BT (1996) The management of gout. N Engl J Med 334: 445–451.
Fang J and Alderman MH (2000) Serum uric acid and cardiovascular mortality the NHANES I epidemiologic follow-up study, 1971–1992. National Health and Nutrition Examination Survey. JAMA 283: 2404–2410.
Ferguson B, Matyszak MK, Esiri MM, and Perry VH (1997) Axonal damage in acute multiple sclerosis lesions. Brain 120: 393–399.
Freedman DS, Williamson DF, Gunter EW, and Byers T (1995) Relation of serum uric acid to mortality and ischemic heart disease. The NHANES I Epidemiologic Follow-up Study. Am J Epidemiol 141: 637–644.
Friedl HP, Till GO, Trentz O, and Ward PA (1991) Role of oxygen radicals in tourniquet-related ischemia-reperfusion injury of human patients. Klin Wochenschr 69: 1109–1112.[CrossRef][Medline]
Gatto EM, Riobo NA, Carreras MC, Chernavsky A, Rubio A, Satz ML, and Poderoso JJ (2000) Overexpression of neutrophil neuronal nitric oxide synthase in Parkinson's disease. Nitric Oxide 4: 534–539.[CrossRef][Medline]
Hediger MA, Johnson RJ, Miyazaki H, and Endou H (2005) Molecular physiology of urate transport. Physiology (Bethesda) 20: 125–133.[CrossRef][Medline]
Hisatome I, Tsuboi M, and Shigemasa C (1996) [Renal hypouricemia]. Nippon Rinsho 54: 3337–3342.[Medline]
Hooper DC, Ohnishi ST, Kean R, Numagami Y, Dietzschold B, and Koprowski H (1995) Local nitric oxide production in viral and autoimmune diseases of the central nervous system. Proc Natl Acad Sci U S A 92: 5312–5316.
Hooper DC, Scott GS, Zborek A, Mikheeva T, Kean RB, Koprowski H, and Spitsin SV (2000) Uric acid, a peroxynitrite scavenger, inhibits CNS inflammation, blood-CNS barrier permeability changes, and tissue damage in a mouse model of multiple sclerosis. FASEB J 14: 691–698.
Hooper DC, Spitsin S, Kean RB, Champion JM, Dickson GM, Chaudhry I, and Koprowski H (1998) Uric acid, a natural scavenger of peroxynitrite, in experimental allergic encephalomyelitis and multiple sclerosis. Proc Natl Acad Sci U S A 95: 675–680.
Inoue S and Kawanishi S (1995) Oxidative DNA damage induced by simultaneous generation of nitric oxide and superoxide. FEBS Lett 371: 86–88.[CrossRef][Medline]
Ischiropoulos H, Zhu L, Chen J, Tsai M, Martin JC, Smith CD, and Beckman JS (1992) Peroxynitrite-mediated tyrosine nitration catalyzed by superoxide dismutase. Arch Biochem Biophys 298: 431–437.[CrossRef][Medline]
Jenner P (2003) Oxidative stress in Parkinson's disease. Ann Neurol 53 (Suppl. 3): S26–S36.[CrossRef][Medline]
Johnson RJ, Kang DH, Feig D, Kivlighn S, Kanellis J, Watanabe S, Tuttle KR, Rodriguez-Iturbe B, Herrera-Acosta J, and Mazzali M (2003) Is there a pathogenetic role for uric acid in hypertension and cardiovascular and renal disease? Hypertension 41: 1183–1190.
Jossa F, Farinaro E, Panico S, Krogh V, Celentano E, Galasso R, Mancini M, and Trevisan M (1994) Serum uric acid and hypertension: the Olivetti heart study. J Hum Hypertens 8: 677–681.[Medline]
Kang DH, Nakagawa T, Feng L, Watanabe S, Han L, Mazzali M, Truong L, Harris R, and Johnson RJ (2002) A role for uric acid in the progression of renal disease. J Am Soc Nephrol 13: 2888–2897.
Kang DH, Park SK, Lee IK, and Johnson RJ (2005) Uric acid-induced C-reactive protein expression: implication on cell proliferation and nitric oxide production of human vascular cells. J Am Soc Nephrol 16: 3553–3562.
Kean RB, Spitsin SV, Mikheeva T, Scott GS, and Hooper DC (2000) The peroxynitrite scavenger uric acid prevents inflammatory cell invasion into the central nervous system in experimental allergic encephalomyelitis through maintenance of blood-central nervous system barrier integrity. J Immunol 165: 6511–6518.
Kim TS, Pae CU, Yoon SJ, Jang WY, Lee NJ, Kim JJ, Lee SJ, Lee C, Paik IH, and Lee CU (2006) Decreased plasma antioxidants in patients with Alzheimer's disease. Int J Geriatr Psychiatry 21: 344–348.[CrossRef][Medline]
Klemp P, Stansfield SA, Castle B, and Robertson MC (1997) Gout is on the increase in New Zealand. Ann Rheum Dis 56: 22–26.
Knapp CM, Constantinescu CS, Tan JH, McLean R, Cherryman GR, and Gottlob I (2004) Serum uric acid levels in optic neuritis. Mult Scler 10: 278–280.
Lee J, Sparrow D, Vokonas PS, Landsberg L, and Weiss ST (1995) Uric acid and coronary heart disease risk: evidence for a role of uric acid in the obesity-insulin resistance syndrome. The Normative Aging Study. Am J Epidemiol 142: 288–294.
Leyva F, Anker SD, Godsland IF, Teixeira M, Hellewell PG, Kox WJ, Poole-Wilson PA, and Coats AJ (1998) Uric acid in chronic heart failure: a marker of chronic inflammation. Eur Heart J 19: 1814–1822.
Lin KC, Lin HY, and Chou P (2000) The interaction between uric acid level and other risk factors on the development of gout among asymptomatic hyperuricemic men in a prospective study. J Rheumatol 27: 1501–1505.[Medline]
Liu F, You SW, Yao LP, Liu HL, Jiao XY, Shi M, Zhao QB, and Ju G (2006) Secondary degeneration reduced by inosine after spinal cord injury in rats. Spinal Cord 44: 421–426.[Medline]
Mazzali M, Hughes J, Kim YG, Jefferson JA, Kang DH, Gordon KL, Lan HY, Kivlighn S, and Johnson RJ (2001) Elevated uric acid increases blood pressure in the rat by a novel crystal-independent mechanism. Hypertension 38: 1101–1106.
Messerli FH, Frohlich ED, Dreslinski GR, Suarez DH, and Aristimuno GG (1980) Serum uric acid in essential hypertension: an indicator of renal vascular involvement. Ann Intern Med 93: 817–821.
Mount DB, Kwon CY, and Zandi-Nejad K (2006) Renal urate transport. Rheum Dis Clin North Am 32: 313–331, vi.[CrossRef][Medline]
Nieto FJ, Iribarren C, Gross MD, Comstock GW, and Cutler RG (2000) Uric acid and serum antioxidant capacity: a reaction to atherosclerosis? Atherosclerosis 148: 131–139.[CrossRef][Medline]
Pacher P, Beckman JS, and Liaudet L (2007) Nitric oxide and peroxynitrite in health and disease. Physiol Rev 87: 315–424.
Perlstein TS, Gumieniak O, Hopkins PN, Murphey LJ, Brown NJ, Williams GH, Hollenberg NK, and Fisher ND (2004) Uric acid and the state of the intrarenal renin-angiotensin system in humans. Kidney Int 66: 1465–1470.[CrossRef][Medline]
Pietraforte D, Castelli M, Metere A, Scorza G, Samoggia P, Menditto A, and Minetti M (2006) Salivary uric acid at the acidic pH of the stomach is the principal defense against nitrite-derived reactive species: sparing effects of chlorogenic acid and serum albumin. Free Radic Biol Med 41: 1753–1763.[CrossRef][Medline]
Puig JG, Michan AD, Jimenez ML, Perez de Ayala C, Mateos FA, Capitan CF, de Miguel E, and Gijon JB (1991) Female gout. Clinical spectrum and uric acid metabolism. Arch Intern Med 151: 726–732.
Puig JG and Ruilope LM (1999) Uric acid as a cardiovascular risk factor in arterial hypertension. J Hypertens 17: 869–872.[CrossRef][Medline]
Radi R, Beckman JS, Bush KM, and Freeman BA (1991) Peroxynitrite-induced membrane lipid peroxidation: the cytotoxic potential of superoxide and nitric oxide. Arch Biochem Biophys 288: 481–487.[CrossRef][Medline]
Radi R, Rodriguez M, Castro L, and Telleri R (1994) Inhibition of mitochondrial electron transport by peroxynitrite. Arch Biochem Biophys 308: 89–95.[CrossRef][Medline]
Rentzos M, Nikolaou C, Anagnostouli M, Rombos A, Tsakanikas K, Economou M, Dimitrakopoulos A, Karouli M, and Vassilopoulos D (2006) Serum uric acid and multiple sclerosis. Clin Neurol Neurosurg 108: 527–531.[CrossRef][Medline]
Saito I, Saruta T, Kondo K, Nakamura R, Oguro T, Yamagami K, Ozawa Y, and Kato E (1978) Serum uric acid and the renin-angiotensin system in hypertension. JAm Geriatr Soc 26: 241–247.[Medline]
Sanchez-Lozada LG, Tapia E, Avila-Casado C, Soto V, Franco M, Santamaria J, Nakagawa T, Rodriguez-Iturbe B, Johnson RJ, and Herrera-Acosta J (2002) Mild hyperuricemia induces glomerular hypertension in normal rats. Am J Physiol Renal Physiol 283: F1105–F1110.
Scott GS, Cuzzocrea S, Genovese T, Koprowski H, and Hooper DC (2005) Uric acid protects against secondary damage after spinal cord injury. Proc Natl Acad Sci U S A 102: 3483–3488.
Scott GS, Spitsin SV, Kean RB, Mikheeva T, Koprowski H, and Hooper DC (2002) Therapeutic intervention in experimental allergic encephalomyelitis by administration of uric acid precursors. Proc Natl Acad Sci U S A 99: 16303–16308.
Simic G, Lucassen PJ, Krsnik Z, Kruslin B, Kostovic I, Winblad B, and Bogdanovi (2000) nNOS expression in reactive astrocytes correlates with increased cell death related DNA damage in the hippocampus and entorhinal cortex in Alzheimer's disease. Exp Neurol 165: 12–26.[CrossRef][Medline]
Smith KJ, Kapoor R, and Felts PA (1999) Demyelination: the role of reactive oxygen and nitrogen species. Brain Pathol 9: 69–92.[Medline]
Spitsin S, Hooper DC, Leist T, Streletz LJ, Mikheeva T, and Koprowskil H (2001a) Inactivation of peroxynitrite in multiple sclerosis patients after oral administration of inosine may suggest possible approaches to therapy of the disease. Mult Scler 7: 313–319.
Spitsin S, Hooper DC, Mikheeva T, and Koprowski H (2001b) Uric acid levels in patients with multiple sclerosis: analysis in mono- and dizygotic twins. Mult Scler 7: 165–166.
Squadrito GL, Cueto R, Splenser AE, Valavanidis A, Zhang H, Uppu RM, and Pryor WA (2000) Reaction of uric acid with peroxynitrite and implications for the mechanism of neuroprotection by uric acid. Arch Biochem Biophys 376: 333–337.[CrossRef][Medline]
Thorns V, Hansen L, and Masliah E (1998) nNOS expressing neurons in the entorhinal cortex and hippocampus are affected in patients with Alzheimer's disease. Exp Neurol 150: 14–20.[CrossRef][Medline]
Toncev G, Milicic B, Toncev S, and Samardzic G (2002) Serum uric acid levels in multiple sclerosis patients correlate with activity of disease and blood-brain barrier dysfunction. Eur J Neurol 9: 221–226.[CrossRef][Medline]
Torun M, Yardim S, Simsek B, and Burgaz S (1998) Serum uric acid levels in cardiovascular diseases. J Clin Pharm Ther 23: 25–29.[CrossRef][Medline]
van der Veen RC, Hinton DR, Incardonna F, and Hofman FM (1997) Extensive peroxynitrite activity during progressive stages of central nervous system inflammation. J Neuroimmunol 77: 1–7.[CrossRef][Medline]
Waring WS, Webb DJ, and Maxwell SR (2000a) Uric acid as a risk factor for cardiovascular disease. Q J Med 93: 707–713.
Waring WS, Webb DJ, and Maxwell SRJ (2000b) Effect of local hyperuricemia on endothelial function in the human forearm vascular bed. Br J Clin Pharmacol 49: 511.
Watanabe S, Kang DH, Feng L, Nakagawa T, Kanellis J, Lan H, Mazzali M, and Johnson RJ (2002) Uric acid, hominoid evolution, and the pathogenesis of salt-sensitivity. Hypertension 40: 355–360.
This article has been cited by other articles:
|
|
 |
|
  P. SOORIAKUMARAN, H. M. COLEY, S. B. FOX, P. MACANAS-PIRARD, D. P. LOVELL, A. HENDERSON, C. G. EDEN, P. D. MILLER, S. E.M. LANGLEY, and R. W. LAING A Randomized Controlled Trial Investigating the Effects of Celecoxib in Patients with Localized Prostate Cancer Anticancer Res, May 1, 2009; 29(5): 1483 - 1488. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. SOORIAKUMARAN, P. MACANAS-PIRARD, G. BUCCA, A. HENDERSON, S.E.M. LANGLEY, R.W. LAING, C.P. SMITH, E.E. LAING, and H.M. COLEY A Gene Expression Profiling Approach Assessing Celecoxib in a Randomized Controlled Trial in Prostate Cancer Cancer Genomics Proteomics, March 1, 2009; 6(2): 93 - 99. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. NEOGI, R. C. ELLISON, S. HUNT, R. TERKELTAUB, D. T. FELSON, and Y. ZHANG Serum Uric Acid Is Associated with Carotid Plaques: The National Heart, Lung, and Blood Institute Family Heart Study J Rheumatol, February 1, 2009; 36(2): 378 - 384. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Frank, T. W. George, J. K. Lodge, A. M. Rodriguez-Mateos, J. P. E. Spencer, A. M. Minihane, and G. Rimbach Daily Consumption of an Aqueous Green Tea Extract Supplement Does Not Impair Liver Function or Alter Cardiovascular Disease Risk Biomarkers in Healthy Men J. Nutr., January 1, 2009; 139(1): 58 - 62. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Anzai, K. Ichida, P. Jutabha, T. Kimura, E. Babu, C. J. Jin, S. Srivastava, K. Kitamura, I. Hisatome, H. Endou, et al. Plasma Urate Level Is Directly Regulated by a Voltage-driven Urate Efflux Transporter URATv1 (SLC2A9) in Humans J. Biol. Chem., October 3, 2008; 283(40): 26834 - 26838. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. H. Proctor Uric Acid and Neuroprotection Stroke, August 1, 2008; 39(8): e126 - e126. [Full Text] [PDF]
|
|
|
|
|
|
A. Bahn, Y. Hagos, S. Reuter, D. Balen, H. Brzica, W. Krick, B. C. Burckhardt, I. Sabolic, and G. Burckhardt Identification of a New Urate and High Affinity Nicotinate Transporter, hOAT10 (SLC22A13) J. Biol. Chem., June 13, 2008; 283(24): 16332 - 16341. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
 |
 |
|
 |
 |
 |
Top
Abstract
Uric Acid Balance