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Molecular Physiology of Urate Transport
Matthias A. Hediger, Richard J Johnson, Hiroki Miyazaki and Hitoshi Endou
20:125-133, 2005. ; Physiology doi: 10.1152/physiol.00039.2004 You might find this additional info useful.
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PHYSIOLOGY 20: 125–133, 2005; 10.1152/physiol.00039.2004
Molecular Physiology of Urate Transport
Matthias A. Hediger Membrane Biology Program and Renal Division, Brigham and Women's Hospital and Harvard Medical School, Humans excrete uric acid as the final breakdown product of unwanted purine Boston, Massachusetts nucleotides. Urate scavenges potential harmful radicals in our body. However, in Richard J Johnson conjunction with genetic or environmental (especially dietary) factors, urate may Division of Nephrology, Hypertension, and Transplantation, University of Florida, Gainesville, Florida cause gout, nephrolitiasis, hypertension, and vascular disease. Blood levels of urate are maintained by the balance between generation and excretion.
Department of Nephrology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan Excretion requires specialized transporters located in renal proximal tubule cells, intestinal epithelial cells, and vascular smooth muscle cells. The recently identi- Department of Pharmacology and Toxicology, Kyorin University School of Medicine, Tokyo, Japan fied human urate transporters URAT1, MRP4, OAT1, and OAT3 are thought to play central roles in homeostasis and may prove interesting targets for future drug development.
Purine nucleotides are the principle constituents of completely elucidated, the likelihood of developing cellular energy stores such as ATP and components gout increases with increased serum urate levels.
of DNA and RNA. In humans, urate is the final Serum concentrations of urate are higher in men breakdown product of unwanted purines because than in women, and gout is therefore more com- higher primates lack the enzyme uricase that, in mon in men. However, only a small proportion of other species, converts urate into allantoin (58, 59) individuals with hyperuricemia [defined by serum (FIGURE 1). The biosynthesis of urate is catalyzed urate concentrations >7 mg/dl (>420 ␮M) in men by xanthine oxidase (XO) and/or its isoform, xan- and >6 mg/dl (>300 ␮M) in women] develop gout.
thine dehydrogenase. Approximately two thirds of It is estimated that 5–10% of adult Americans have the daily turnover of urate is accounted for by uri- hyperuricemia, whereas only 20% of this popula- nary excretion, with the remaining one third being tion develop gout (51, 52). In some cases, gout is excreted into the gut as feces (48). In the setting of even observed with "normal" uric acid levels.
oxidative stress, some urate may also be oxidized to Therefore, hyperuricemia is often not sufficient for allantoin or other breakdown products, such as expression of gout, and additional genetic or envi- parabanate and alloxan (13, 56). In the human kid- ronmental risk factors are involved, including ney, urate is reabsorbed and secreted via recently hypertension, the use of thiazides and loop diuret- identified urate transporters.
ics, obesity, and a high alcohol intake (7).
Although urate may have beneficial effects, since Gout emerged as an epidemic in 18th and 19th it scavenges potential harmful radicals in our body century England, where it was considered a disease (1, 5), in conjunction with genetic or environmental of the wealthy because it seemed to be caused by factors it can cause significant health problems, eating rich foods and drinking too much alcohol.
including complications associated with urate crys- Indeed, purine content in the diet is one of the fac- tals such as kidney stones and gout. There is also tors that affect the body load of urate. The magni- increasing evidence that subjects with elevated uric tude of this contribution depends on the amount acid may be at increased risk for cardiovascular and and type of purine in the diet, but it is often con- renal disease and that this may be mediated by uric siderable. Foods high in purine include anchovies, acid via a crystal-independent mode of action. The sardines, herring, trout, organ meats (liver, heart, levels of urate in the blood are dependent on the kidney), meat gravies, broths, asparagus and balance of generation and excretion. Normally, the mushrooms. The effect of alcohol is in part related body eliminates enough urate in the kidney and in to increased urate synthesis, which is due to part also in the intestines, keeping its blood con- enhanced turnover of ATP during the conversion of centration between 240 and 350 ␮M (FIGURE 1). In acetate to acetyl-CoA as part of the metabolism of people with gout or kidney stone disease, however, ethanol (16). Also, acute alcohol consumption the body either produces excessive amounts of causes lactate production, and because lactate is urate or its ability to eliminate urate is disturbed.
an antiuricosuric agent, it will reduce renal urateexcretion and exacerbation of hyperuricemia (see Gout and Hyperuricemia
Identification and characterization of URAT1). Inaddition, part of the association of alcohol intake Although the mechanism of gout has not been with gout is likely related to the high lead content in 1548-9213/05 8.00 2005 Int. Union Physiol. Sci./Am. Physiol. Soc.

certain liquors during this era, particularly in port Gout may be either primary (e.g., genetic) or sec- wines. Lead is known to cause a marked rise in ondary (due to a condition known to cause hyper- serum uric acid by impairing urate excretion and uricemia). The pathogenesis of gout is character- has been associated with the development of gout ized by sodium urate crystal precipitation in tis- (termed "saturnine gout").
sues, in particular in the joints of hyperuricemic More recently, gout has been observed in the patients. This is followed by phagocytosis of the general population, both in industrialized and crystals by neutrophils and macrophages and acti- developing countries. Its marked rise in prevalence vation of acute inflammation and tissue injury. The in certain populations, such as the African solubility of urate decreases with decreasing tem- American and the Maori, correlate with the rise in perature, explaining the increased incidence of obesity in these populations. Although some of this gout in peripheral joints, which are cooler.
increased frequency likely relates to increased However, what exactly initiates crystallization of ingestion of fatty meats high in purine content, it is urates in joints and why certain peripheral joints also important to note that dietary fructose acutely are preferentially involved is still unknown.
raises serum uric acid levels (14, 19, 22, 41, 50).
Treatment of gout
Fructose is phosphorylated by fructokinase in hepatocytes with generation of ADP, which leads to There are three main types of drugs used in treating the rapid production of urate (20). Fructose is a gout and hyperuricemia. Allopurinol (Lopurin, major component of table sugar (sucrose) as well Zyloprim), which is readily absorbed after oral as high fructose corn syrup, which is a frequently intake, is used effectively for treatment of patients used sweetener. It is thus likely that the progressive with primary hyperuricemia and gout. Allopurinol rise in serum uric acid within the US and other acts as a competitive inhibitor of XO, blocking the populations over the last century may in part relate synthesis of urate in the liver and other organs and to a change in eating habits associated with reducing the amount of urate in the body.
increased intake of purine-rich foods, fructose, and Nonsteroidal anti-inflammatory drugs, cortico- steroids, and colchicine help relieve the symptoms Purines, fructose, alcohol De novo purine synthesis Purine catabolism Cellular degradation: leukemia, lymphomas, chemotherapy (strenuous exercise) FIGURE 1. Human urate
homeostasis
Urate is produced as the
major end product of purine
metabolism by liver, muscles, and intestine. The biosynthe- sis of urate is catalyzed by xanthine oxidase (XO).
Approximately two thirds ofthe daily turnover of urate is accounted for by urinary excretion, with the remaining one third beingexcreted into the gut as feces. In the human kidney, filtered urate is reabsorbed via the transporter URAT1. To alesser extent, urate may also be secreted directly into the tubular lumen via the MRP4 pump. Dietary fructose, alcoholconsumption, and cellular degradation can furthermore increase urate levels (see text for details). The production allan-toin and related compounds may occur in tissues, such as vascular smooth muscle cells, as a result of nonenzymatic reac-tions of urate with reactive oxygen species (13).
PHYSIOLOGY • Volume 20 • April 2005 • www.physiologyonline.org of gout by reducing inflammation. Probenecid sis of inosine from ribose-1-phosphate. The catab- (Benemid, Probalan), sulfinpyrazone (Anturane), olism of inosine then results in hypoxanthine via and benzbromarone (Urinorm) are uricosuric purine nucleoside phosphorlyase and then xan- drugs (see Identification and characterization of thine and urate via XO, a flavoprotein that contains URAT1) that help the body to get rid of excess urate iron and molybdenum. In humans, XO is found to in the kidneys. In addition, rasburicase (Elitek; be highly expressed in the liver and also to a lesser Sanofi-Synthélabo) is a genetically derived urate extent in the mucosa of the small intestine. On the oxidase. Administration of rasburicase rapidly con- basis of its tissue distribution, urate synthesis verts poorly soluble urate into highly soluble allan- appears to be largely a hepatic process in humans.
toin, which is readily excreted by the kidneys and When there is massive tissue breakdown, there may prevents acute hyperuricemia and renal failure.
be a substantial release of DNA and RNA, resulting This product has been approved by the US Fand in a large purine load to the liver, followed by a Drug Administration for the initial management of marked rise in serum urate levels. The most com- plasma uric acid levels in pediatric patients with mon cause is accelerated cell turnover or cell lysis leukemia, lymphoma, and solid tumor malignan- resulting from chemotherapy or radiation therapy, cies who are receiving anticancer therapy expected especially in leukemia and lymphoma. This condi- to result in tumor lysis.
tion, termed "tumor lysis syndrome," results in arapid increase of urate plasma levels, followed by a Uric Acid Stones
marked increase in urinary urate concentrations.
This in turn results in intratubular crystallization Uric acid stones account for 5–10% of urinary with obstruction and acute renal failure (ARF).
stones. Uric acid stones may contain pure uric acid Local inflammation (including giant cell forma- or a combination of calcium and urate.
tion) and interstitial fibrosis may result if the Hyperuricosuria, which is defined as urinary obstruction is prolonged. Treatment may require excretion of urate >800 mg/day in men and >750 acute hemodialysis as well as hydration and alka- mg/day in women, can be a cause of stone forma- linization of the urine to improve urate solubility.
tion. It may be due to either excessive dietary Rasburicase is also commonly used to acutely intake of purine-rich foods or endogenous urate lower urate levels.
overproduction. Approximately 15–20% of ARF may also accompany idiopathic renal hype- patients with calcium stones have hyperurico- ruricemia. This is a rare condition due to a defect in suria. Uric acid may initiate calcium oxalate stone renal urate reabsorption (see Identification and formation by the induction of heterogeneous characterization of URAT1) and has been particu- nucleation. Also, hyperuricosuria may be associat- larly observed in the Japanese population.
ed with hyperuricemia, and up to 20% of patients Although the pathogenesis of ARF has not been with gout develop urate stones. However, uric acid entirely elucidated, it has been reported to be pre- stones may also occur in patients with normal uri- cipitated by strenuous exercise. It remains possible nary and serum levels of urate. Uric acid stones that the mechanism involves exercise-induced can generally be managed with alkalization of the rhabdomyolysis leading to increased urate genera- urine to pH 6.0–6.5, for example with oral potassi- tion that then results in high urinary urate levels um citrate. Urate is far more soluble than uric acid.
with intratubular crystallization and obstruction.
Only the first proton dissociation (pK = 5.75) need be considered here, since pK for the second pro- Purine and Nitrogen Metabolism
ton is 10.3, a value well above the physiologicalrange (see FIGURE 1, INSET). The pH of the fluid in In certain species, purines assume the additional the proximal tubule is approximately the same as function of secreting nitrogen waste. Organisms that of plasma, and this compound will therefore that excrete urate are called "uricotelic" (e.g., be mostly in the monovalent urate form.
birds, terrestrial reptiles, insects). In contrast, Acidification is a distal tubular function, and the organisms that excrete urea are called "ureotelic" pH of normal urine typically is below 5.8. Thus (e.g., elasombranch fish, mammals), and organ- stones of the urinary collecting system are uric isms that excrete ammonia are called acid stones whose formation can be reduced by "ammonotelic" (e.g., most aquatic invertebrates).
alkalinization of the urine.
Although more energy is required to produceurate compared with urea and ammonia, the ben- Acute Urate Nephropathy
efit of urate is that less water is needed to excretethis compound. Birds, terrestrial reptiles, and In addition to purine derived from dietary sources, insects use urate both as a nitrogen waste product there is extensive de novo purine synthesis in the and as a purine metabolism end product. Most body, primarily in the liver, which involves synthe- mammals use urea as their major nitrogen end PHYSIOLOGY • Volume 20 • April 2005 • www.physiologyonline.org product and secrete allantoin as the end product Mechanisms of Renal Urate
of purine metabolism. Humans and apes, howev- er, lack the enzyme uricase that converts urate toallantoin (58, 59). They use urea as the major In the kidney, filtered urate is greatly reabsorbed in nitrogen end product, and urate is the end prod- the proximal tubules in humans but is secreted into uct of purine metabolism.
the tubule fluid in other species. The reabsorptionand secretion processes depend on specific trans- Beneficial Effects of Urate
porter molecules that reside in these membranes.
Based on membrane vesicle studies, the existence Urate accumulation in man and higher primates of two transporters, a voltage-sensitive pathway has been proposed to have evolutionary advan- and a urate/anion exchanger, have been predicted tages. Similar to vitamin C, urate is a potent antiox- in the renal proximal tubules (45).
idant (1, 5). Based on the fact that birds are very Identification and characterization of
long-lived for their body size—despite high meta- bolic rates, high body temperatures, and highblood glucose levels—it has been suggested that The transporter that reabsorbs urate has been urate could contribute to the increased lifespan of recently identified by Enomoto et al. and was primates compared with other vertebrates (11, 47).
named URAT1 (SLC22A12) (15). URAT1 belongs to Also, urate can maintain blood pressure under low- the organic ion transporter family (SLC22) (35) (see salt conditions via stimulation of the renin- angiotensin system through a mechanism that is URAT1 consists of 555 amino acid residues and 12 still poorly understood (37, 38, 40, 46, 57).
predicted putative transmembrane domains Furthermore, recent studies (49, 53) suggest that (TMs), with large hydrophilic loops between the urate may help arrest multiple sclerosis through first and second as well as the sixth and seventh scavenging the toxic compound peroxynitrite in TMs and intracellular NH and COOH terminals the central nervous system. Humans reabsorb (FIGURE 2). Similar to other SLC22 members, sev- urate very efficiently to maintain relatively high eral PKA and PKC phosphorylation sites are pre- blood levels of urate. The enhanced mechanism for dicted in the large intracellular hydrophilic loop urate reabsorption via the URAT1 transporter (see between the sixth and seventh TMs.
Identification and characterization of URAT1), the URAT1 is expressed in the apical membrane of decrease in renal urate secretion, and the loss of proximal tubule cells (FIGURE 3). In human kidney, uricase during hominoid evolution account for the urate is transported via URAT1 across the apical higher levels of urate in human blood (180–720 membrane of proximal tubule cells, in exchange for ␮M) compared with mammals that have uricase anions being transported back into the tubule (30–120 ␮M) (28).
lumen to maintain electrical balance. Urate then FIGURE 2. Proposed
membrane topology
model of the
urate/anion exchanger
URAT1 (SLC22A12)
The transporter has 12
putative transmembrane domains and a PDZ bind- ing motif at the COOH terminus. PKA and PKC,protein kinases A and C, PHYSIOLOGY • Volume 20 • April 2005 • www.physiologyonline.org moves across the basolateral membrane into the Proximal tubule cell blood by another organic anion transporter. URAT1is presumably absent in other mammals such asrabbits and pigs, as these species predominantly secrete urate. But in humans, urate secretion is probably negligible and URAT1 is thought to be the major mechanism for regulating blood urate levels. Consistent with this, mutations of SLC22A12 cause idiopathic renal hypouricemia (15, 25). This is a rare disorder with a prevalence of 0.12% (with higher frequencies in Japanese and Iraqi Jews). As discussed above, it is primarily characterized byexercise-induced ARF, triggered by the increasedproduction of urate and reactive oxygen speciesthat occurs in muscle during exercise (34). The lackof a functional URAT1 transporter results in lower FIGURE 3. Urate transport in the human renal
blood levels of urate and high urinary urate levels, In humans, net reabsorption of urate predominates resulting in crystal formation within the kidney because they excrete less urate than is filtered at the tubules. This, together with exposure of the kidneys glomerulus. The following urate transporters have beenidentified in human kidney: URAT1, MRP4, OAT1, and to reactive oxygen species generated during exer- OAT3. URAT1, an apical urate/anion exchanger, is cise, causes death of tubule cells. Without exercise, responsible for renal urate reabsorption. OAT1 and however, these patients can live normally, except OAT3 are basolateral urate transporters. They are organ- ic anion/dicarboxylate exchangers and may be involved for an increased occurrence of kidney stones.
in basolateral urate uptake. Whether there is a separate Genetic examinations of SLC22A12 in Japanese basolateral urate exit mechanism is still unknown. MRP4 patients with idiopathic renal hypouricemia is an apical, ATP-dependent urate export transporter.
OAT1/3 and MRP4 likely participate in transcellular urate revealed that 2 out of 32 patients did not have mis- secretion. OATv1 (not shown) is another proposed apical sense mutations in this gene (25). This suggests urate exit transporter, but a human ortholog does not that additional genes related to urate transport or appear to exist. PZA, pyrazinamide.
metabolism could be involved in the pathogenesis,although the possibility of altered promoter func- phosphorylation sites, and thus studying the phos- tion of SLC22A12 has not yet been addressed.
phorylation of URAT1 will be of great importance.
URAT1 interacts with a wide variety of therapeu- It is also increasingly recognized that membrane tic drugs and pharmacological reagents. For exam- transport proteins are regulated through protein- ple, drugs that are used to treat inflammation or protein interaction at the plasma membrane. Of high blood pressure have undesirable side effects particular interest, URAT1 possesses a PDZ motif at on urate excretion (45). By definition, "uricosuric" its COOH terminus (FIGURE 2). PDZ motifs are drugs such as probenecid, benzbromarone, the protein-protein interaction modules that are com- anti-inflammatory drug sulfinpyrazone, the anti- posed of three amino acid residues, (S/T)-X-␾ hypertensive drug losartan, and the loop diuretic (where X is any amino acid and ␾ is a hydrophobic furosemide increase urate secretion, whereas residue). PDZ motifs bind to PDZ domains, which "antiuricosuric" drugs such as pyrazioic acid (the are 80–90 amino acids in length and are typically metabolite of the antituberculous agent pyrazi- expressed in multiple copies within PDZ proteins.
namide), nicotinate, and lactate decrease urate These are multidomain proteins that not only tar- secretion. In general, Enomoto et al. (15) found that get and provide scaffolds for protein-protein inter- uricosuric drugs directly inhibit URAT1 from the actions but also modulate the function of the asso- apical side, whereas antiuricosuric drugs serve as ciation proteins (24). Also, PDZ proteins are the exchanging anion from inside tubule cells, thought to cluster membrane proteins such as thereby enhancing urate transport by URAT1 transporters, channels, and receptors within sub- through trans-stimulation. The inhibitory (urico- cellular domains to coordinate their activity.
suric) or stimulating (antiuricosuric) effects of the A recent study demonstrated that URAT1 inter- different drugs was evaluated by using Xenopus acts with the multivalent PDZ domain-containing oocyte expression analysis.
protein PDZK1 via its COOH-terminal PDZ motifs(2). PDZK1 was first identified from rat kidney in Regulation of URAT1
1997 (10) and possesses four tandem PDZ domains.
Because URAT1 controls the blood urate level, it is Immunohistochemical analyses revealed that important to clarify the regulatory mechanisms of URAT1 and PDZK1 are colocalized at the apical URAT1. One possibility is the regulatory system via membrane of renal proximal tubular cells (2). This phosphorylations. URAT1 possesses PKA and PKC interaction required the PDZ motif and the first, PHYSIOLOGY • Volume 20 • April 2005 • www.physiologyonline.org second, and fourth PDZ domains of PDZK1. The age-sensitive luminal exit pathway that was pre- importance of the PDZ motif in this interaction was dicted based on vesicle studies (45). However, a also confirmed by in vitro glutathione-S-trans- human ortholog of OATv1 has not been identified ferase pull-down assay as well as co-immunopre- thus far. Also, OATv1 shares some similarity with cipitation using human embryonic kidney 293 human NPT1/SLC17A1 (see http://www.biopara- cells. Coexpression of PDZK1 and URAT1 in 293 digms.org/slc/SLC17.htm). This transporter may cells increased urate transport by URAT1 1.4-fold, play a primary role in species like rabbits and pigs and deletion of the COOH-terminal PDZ motif of that regulate their blood uric acid level mainly by URAT1 abolished this effect. This indicates that PDZK1 regulates URAT1 transport activity via PDZ Species difference in renal handling of urate has always be an unsolved problem in renal physiology Studies addressing the hormonal regulation of (12, 45). The molecular identification of urate URAT1 are also needed for a better understanding transporters is beginning to provide answers and of the molecular mechanisms of urate transport in clues to this problem. Net reabsorption predomi- the kidney. Recently, a mouse homolog of URAT1 nates in humans, dogs, and rats, which excrete less was identified (GenBank accession no. AC124394) urate than is filtered at the glomerulus, and net (23), and Western blot analysis revealed that URAT1 secretion predominates in rabbits, pigs, and birds, expression levels are higher in male mice com- which excrete more urate than is filtered at the pared with female mice, suggesting that URAT1 glomerulus. It is not unexpected, therefore, that transcription is regulated by sex hormones. It is urate transporters involved in secretion are absent well known that blood urate levels are sex depend- or expressed at low levels in urate "reabsorbers," ent and that estrogen increases the renal urate whereas urate transporters involved in reabsorp- excretion. Promoter analyses of URAT1 will be tion are present at low levels in urate "secretors." required to address this hypothesis.
This appears to be true for pig OATv1 and human To further advance our understanding of the URAT1, which mediate urate secretion and reab- physiological roles of urate, the generation of sorption, respectively. However, although filtered URAT1 knockout mice will be useful. For this pur- urate is almost completely reabsorbed in humans pose, it would be necessary to delete both uricase through URAT1, renal hypouricemic patients with and URAT1 to mimic the lack of uricase in humans.
defective URAT1 (which reabsorb <10% of filteredurate) were shown to exhibit urate excretion that Mechanisms of Urate Secretion
exceeds the glomerular filtration rate (34). Giventhat proximal tubules hardly produce urate, this Despite the recent progress in the understanding of finding clearly indicates that there must be a urate urate transport, there are still many open ques- secretion process in human kidney.
tions. The identification of URAT1 only accounts Efflux pump MRP4
for part of the urate transport system in the kidney.
For example, the basolateral exit pathway of urate Recently, a novel human renal apical organic anion in proximal tubule is still unknown. The organic efflux transporter, called MRP4, has been identified anion transporters OAT1 (SLC22A6) and OAT3 (54). MRP4 is a member of the ATP-binding cas- (SLC22A8) (9) probably mediate basolateral urate sette transporter family. It is proposed to mediate uptake, as both transporters function as organic secretion of urate and other organic anions such as anion/dicarboxylate exchangers (FIGURE 3) and cAMP, cGMP, and methotrexate across the apical both have been shown to transport urate (4, 26).
membrane of human renal proximal tubular cells.
Given the outwardly directed electrochemical Human MRP4 is an ATP-dependent unidirectional dicarboxylate gradient that is maintained by the efflux pump for urate with multiple allosteric sub- apical and basolateral sodium/dicarboxylate trans- strate binding sites (55).
porters SLC13A2 and SLC13A3, respectively, it is MRP4 is furthermore expressed in the basolater- likely that OAT1 and OAT3 contribute to basolater- al membrane of hepatocytes, where it is presumed al urate uptake rather than efflux.
to mediate hepatic export of urate into the circula-tion. Whether similar mechanisms are in place for Efflux transporter OATv1
the excretion of urate in the intestine (FIGURE 1) Recently, an apical, voltage-driven, organic anion remains to be elucidated.
efflux transporter termed OATv1 was isolated froma porcine kidney cDNA library (29). OATv1 is a new Other Proteins Involved in Renal
member of the SLC17 vesicular glutamate trans- porter family. The ability of OATv1 to transport urate was confirmed by Xenopus oocyte expressionstudies. OATv1 is thought to correspond to the volt- Another gene involved in renal transport of urate is PHYSIOLOGY • Volume 20 • April 2005 • www.physiologyonline.org Tamm-Horsfall protein (THP), also known as uro- markedly elevated serum levels (>350–400 ␮M) due modulin (43). THP is exclusively expressed in to a combination of genetic or environmental epithelial cells of the thick ascending limb. It is the (especially dietary) factors may be detrimental. In most abundant protein in urine. Mutations in the addition to the risk for gout and nephrolithiasis, human uromodulin gene result in hyperuricemia there is increasing evidence that hyperuricemia and reduced urinary concentrating ability. Such may also be involved in the pathogenesis of hyper- mutations are the cause of glomerulocystic kidney tension, vascular disease, and renal failure (27).
disease and medullary cystic disease/familial juve- Experimental hyperuricemia in rats has been nile hyperuricemic nephropathy (6, 43). Many of shown to result in hypertension via a mechanism the uromodulin mutations likely affect protein involving alterations in endothelial function, acti- folding, resulting in intracellular aggregation and vation of the renin-angiotensin system, and the accumulation and thereby reducing the excretion development of microvascular disease (27, 33, 37, of uromodulin in the urine. The exact mechanism 39, 57). Intrarenal arteriolar disease develops in by which uromodulin affects urate secretion is still these animals and appears to be mediated via a unknown. One possibility is that mutations in THP direct effect of urate on the vascular smooth mus- affect sodium reabsorption in the thick ascending cle cell (39). Specifically, it has been shown that limb, because this part of the kidney is known to urate enters rat vascular smooth muscle cells via an interact with the Na+-K+-2Cl– cotransporter organic anion transporter (21), where it then acti- NKCC2. This could result in both a defect in water vates ERK1/2 (57) and p38 (30) MAP kinases, NF-␬B concentration and sodium conservation. A conse- and AP-1 nuclear transcription factors (30), PDGF quence of a defect of this nature would be an A- and C-chain mRNA (44, 57), COX-2 mRNA, upregulation of proximal mechanisms for sodium thromboxane (32), and monocyte chemoattractant reabsorption, which would be predicted to increase protein-1 (MCP-1) (30). This results in proliferation urate reabsorption (8). Recent studies of THP of the vascular smooth muscle cell and the release knockout mice revealed that these animals exhibit of inflammatory mediators (especially MCP-1).
increased expression of major distal electrolyte Similarly, urate has been shown to activate human transporters, whereas juxtaglomerular cyclooxyge- vascular smooth muscle cells and to induce cell nase-2 (COX-2) and renin expression was proliferation, stimulating production and release decreased compared with wild-type mice (3). The of C-reactive protein and inducing upregulated THP knockout mice did not develop hyper- expression of the angiotensin II type 1 receptor uricemia, nor do they get renal failure. Whether fractional urate reabsorption is increased in these The specific transporter that mediates the animals still remains to be determined.
uptake of urate into the vascular smooth musclecell is not known, although the possibility that it is URAT-1 has been supported by the recent demon- UAT has also been proposed to be involved in renal stration that both human aortic and renal afferent urate transport (36). UAT was identified by screen- vascular smooth muscle cells express both the ing a rat kidney cDNA library with a polyclonal mRNA and the protein (42).
antibody to pig liver uricase, and its function was In addition to effects on vascular smooth muscle examined by using a reconstitution assay. UAT is cells, urate also inhibits endothelial cell prolifera- expressed ubiquitously and localizes to the apical tion (18) and reduces endothelial nitric oxide levels side of the proximal tubule in the kidney. It consists (33). Thus, experimentally, uric acid may have both of 322 amino acid residues and contains 4 trans- systemic effects (inhibition of systemic nitric oxide membrane-spanning domains, with a predicted levels and activation of the renin-angiotensin sys- urate binding site on the intracellular loop between tem) and direct cellular effects (on vascular smooth transmembrane domains 2 and 3. Consequently, muscle cells and endothelial cells) that may be UAT is supposed to be a multimeric protein.
responsible for causing both hypertension and Interestingly, UAT is identical to galectin 9, whose renal microvascular disease (57). Interestingly, function has been related to various functions that, although the effect of experimental hyperuricemia at a first glance, appear to be unrelated to urate to cause hypertension can be prevented by lower- transport. Further studies are needed to determine ing uric acid, once significant renal microvascular the precise role of UAT/galectin 9 in urate metabo- disease is induced, the hypertension is then medi- ated by the kidney and becomes salt sensitive anduric acid independent (37, 57).
Urate, Hypertension, and Vascular
Studies in humans also show that elevated urate levels predict the development of hypertension(reviewed in Ref. 27). In new-onset essential hyper- Urate clearly has many beneficial effects. However, tension in adolescents, the correlation between PHYSIOLOGY • Volume 20 • April 2005 • www.physiologyonline.org 13. Doehner W, Schoene N, Rauchhaus M, Leyva-Leon F, Pavitt urate levels and blood pressure is remarkable (r = DV, Reaveley DA, Schuler G, Coats AJ, Anker SD, andHambrecht R. Effects of xanthine oxidase inhibition with 0.8, P < 0.01) with an elevated uric acid level pres- allopurinol on endothelial function and peripheral blood flow ent in 89% of subjects vs. 0% in 63 controls (17). In in hyperuricemic patients with chronic heart failure: resultsfrom 2 placebo-controlled studies. Circulation 105: pilot studies, the lowering of uric acid in adoles- 2619–2624, 2002.
cents with new-onset hypertension resulted in nor- 14. Emmerson BT. Effect of oral fructose on urate production.
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