Hyperuricemia, Gout, and the Kidney

Duk-Hee Kang

Mehmet Kanbay

Richard Johnson

Uric acid is a weak acid trioxopurine with a molecular weight of 168 that is composed of a pyrimidine and imidazole substructure with oxygen molecules (C₅H₄N₄O₃). It is produced during the metabolism of purines, and specifically is generated by the degradation of xanthine by the enzyme xanthine oxidase or its isoform, xanthine dehydrogenase. In most mammals uric acid is oxidized to 5-hydroxyisourate by the hepatic enzyme, urate oxidase (uricase), which is then further hydrolyzed to allantoin.¹ However, during early hominoid evolution (12 to 20 million years ago) a series of mutations occurred, first affecting the promoter region and then the actual gene, eventually rendering uricase nonfunctional.²,³ As a consequence, serum uric acid levels in humans are higher (3 to 15 mg per dL, 180 to 900 µM) and less regulatable than in most mammals (1 to 3 mg per dL, 60 to 180 µM).⁴ Great apes (such as the chimpanzee, gorilla, and orangutan) share the same uricase mutation as humans, and lesser apes (gibbons and siamangs) have a different uricase mutation, but these apes have lower serum uric acid levels (2 to 4 mg per dL, 120 to 240 µM),⁴ primarily due to diets relatively low in purines and fructose.

The most well-known consequence of an elevated uric acid in humans is the disease gout, due to the deposition of urate crystals in synovial joints, occasionally with tophi formation. However, there are also a number of renal manifestations associated with elevated uric acid, including the formation of uric acid kidney stones (urate nephrolithiasis), acute urate nephropathy (due to intratubular crystal formation with obstruction), and chronic urate (“gouty”) nephropathy. The latter has been historically viewed as occurring as a consequence of interstitial urate crystal deposition with local inflammation; however, there is increasing evidence suggesting this entity may also result from crystal-independent effects of uric acid. There is also the entity of familial juvenile hyperuricemic nephropathy (FJHN), for which the gene responsible has been identified. Recent studies also suggest that uric acid may have a role in other renal diseases and may also have a direct role in mediating intrarenal vascular disease, hypertension, and even the metabolic syndrome. These are all discussed in subsequent text of this chapter.

URATE METABOLISM AND HOMEOSTASIS

Generation of Uric Acid

Uric acid is produced from metabolic conversion of either dietary or endogenous purines, primarily in the liver, muscle, and intestine (Fig. 61.1).⁵ Uric acid can also be produced de novo from glycine, glutamine, and other precursors. The immediate precursor of uric acid is xanthine, which is degraded to uric acid by either xanthine oxidase, which generates superoxide anion in the process, or by its isoform, xanthine dehydrogenase, which generates the reduced form of nicotinamide-adenine dinucleotide. Both exogenous purines (such as is present in fatty meat, organ meats, and seafood) and endogenous purines are major sources of uric acid in humans. Approximately two thirds of total body urate is produced endogenously, whereas the remaining one third is accounted for by dietary purines. Purine-rich foods include beer and other alcoholic beverages, anchovies, sardines in oil, fish roes, herring, organ meat (liver, kidneys, sweetbreads), legumes (dried beans, peas), meat extracts, consommé, gravies, mushrooms, spinach, asparagus, and cauliflower.⁶ In healthy men, the urate pool averages about 1,200 mg with a mean turnover rate of 700 mg per day.

Excretion of Uric Acid

The primary site of excretion of uric acid is the kidney, with normal urinary urate excretion in the range of 250 to 750 mg per day. Although urate (the form of uric acid at blood pH of 7.4) is freely filtered in the glomerulus, there is evidence that there is both reabsorption and secretion in the proximal tubule, and as a consequence the fractional urate excretion is only 8% to 10% in the normal adult because urate reabsorption dominates oversecretion in the kidney. Some adaptation occurs with renal disease, in which the fractional excretion will increase to the 10% to 20% range. In addition, uric acid is also removed by the gut, where uric acid is degraded by uricolytic bacteria, and this may account for one third of the elimination of uric acid in the setting of renal failure.

FIGURE 61.1 Urate metabolism.

The historic paradigm of uric acid excretion consists of a four-step model with glomerular filtration, followed by reabsorption, secretion, and postsecretory reabsorption, the latter three processes all occurring in the proximal convoluted tubule.⁷,⁸ However, ideas of the handling of uric acid by the kidney have changed greatly during the last decades, with characterization and isolation of transporters and channels mainly or exclusively restricted to urate transport (Fig. 61.2).⁹,¹⁰ Membrane vesicle studies have suggested the existence of two major mechanisms modulating urate reabsorption and secretion, consisting of a voltage-sensitive pathway and a urate/organic anion exchanger. Recently several of these transporters/channels have been identified. Organic anion transporters 1-10 (OAT1-10) and the urate transporter-1 (URAT-1) belong to the SLC22A gene family and accept a huge variety of chemically unrelated endogenous and exogenous organic anions including uric acid. Endou’s group identified URAT-1, which is encoded by SLC22A12, as the major organic anion exchanger for uric acid on the apical (luminal brush border) side of the proximal tubular cell.⁹ In the human kidney, urate is transported via URAT-1 across the apical membrane of proximal tubular cells, in exchange for anions being transported back into the tubular lumen to maintain electrical balance. URAT-1 has a high affinity for urate together with lactate, ketones, a-ketoglutarate, and related compounds. Pyrazinamide, probenecid, losartan, and benzbromarone all inhibit urate uptake in exchange for chloride at the luminal side of the cell by competition with the urate exchanger. OAT-4 exhibits 53% amino acid homology with URAT1.

Urate then moves across the basolateral membrane into the blood by other organic anion transporters, of which the most important is SLC2A9 (also known as GLUT9).¹¹,¹² GLUT-9 is highly expressed in the kidney and liver. GLUT-9L (long isoform) is localized to basolateral membranes in proximal tubule epithelial cells, whereas the splice variant GLUT-9S (short isoform) localizes to apical membranes (Fig. 61.2).¹³ Vitart et al.¹⁴ showed that GLUT-9 transports urate and fructose, using a Xenopus oocyte expression system. GLUT-9 deficiency resulted in renal hypouricemia and is consistent with GLUT-9 being an efflux transporter of intracellular urate from the tubular cell to the interstitium/blood space.¹⁵ Efflux transport of urate at basolateral membranes appears to depend principally on GLUT-9L whereas URAT-1 mainly acts as an influx transporter for urate at apical membranes.

OAT-4 and OAT-10 function as an organic anion/dicarboxylate exchanger and are responsible for the reabsorption of organic anions driven by an outwardly directed dicarboxylate gradient.¹⁶ In addition, OAT1 and OAT3 may have a role in the transport of urate from the blood into the proximal tubule.¹⁷,¹⁸

Urate secretion appears to be mediated principally by a voltage-sensitive urate transporter, which is expressed ubiquitously and localizes to the apical side of the proximal tubule in the kidney. Genomewide association studies revealed the region which is related to serum urate concentration.¹⁹ Recently, a novel human renal apical organic anion efflux transporter, called MRP4, has been identified.²⁰ MRP4 is a member of the ATP-binding cassette transporter family. It is proposed to mediate secretion of urate and other organic anions such as cAMP, cGMP, and methotrexate across the apical membrane of human renal proximal tubular cells. Human MRP4 is an ATP-dependent unidirectional efflux pump for urate with multiple allosteric substrate binding sites.²¹ Renal sodium-dependent phosphate transport protein-1 (NPT-1),²² which was first cloned as a phosphate transporter, is located in the proximal
convoluted renal tubule (Fig. 61.2). NPT1 mediates voltage-sensitive transport of organic anions, including urate, and is suggested to function as a urate secretor.²³ Another transporter located at the apical membrane of proximal tubules is ATP-binding cassette, sub-family G, member 2 (ABCG2). The ability of ABCG2 to transport urate was recently confirmed by measuring urate efflux from ABCG2-expressing Xenopus oocytes.²⁴

FIGURE 61.2 Urate transport. (From Ichida K. What lies behind serum urate concentration? Insights from genetic and genomic studies. Genome Med. 2009;1(12):118.)

Another gene involved in renal transport of urate is Tamm-Horsfall protein (THP), also known as uromodulin. THP is exclusively expressed and secreted by epithelial cells of the thick ascending limb, where it has been shown to have antibacterial effects. THP also co-localizes with the Na-K-2Cl transporter in lipid rafts in the apical cell membrane, suggesting a functional interaction.²⁵ Mutations in the human uromodulin gene have been identified in subjects with medullary cystic kidney disease type 2 and in patients with familial juvenile hyperuricemic nephropathy (see subsequent text).²⁶,²⁷ It is not yet known how the THP mutation leads to hyperuricemia, as most evidence suggests that uric acid handling is restricted to the proximal tubule. However, there is some evidence that some urate secretion in the rat can occur distal to the proximal tubule.²⁸ Furthermore, there is also some evidence that the THP mutation may lead to sodium and water wasting, possibly resulting in stimulating urate reabsorption proximally (see following section on Familial Juvenile Hyperuricemic Nephropathy).

Causes of Hyper- and Hypouricemia

Hyperuricemia has been arbitrarily defined as >7.0 mg per dL in men and >6.5 mg per dL in women. “Normal” serum uric acid levels in the population appear to be rising throughout the last century, likely as a consequence of changes in diet, and mean levels in men in the United States are now in the 6.0 to 6.5 mg per dL range.⁴ Uric acid levels tend to be higher in certain populations (e.g., African American and Pacific Islanders), with certain phenotypes (obesity, metabolic syndrome) and with special diets (meat eaters).⁴ Uric acid also has a circadian variation, with the highest levels in the early morning.²⁹

The serum urate concentration reflects the balance between urate production and elimination. Hyperuricemia may occur from excessive production of urate (overproduction) or decreased elimination (underexcretion), and frequently a combination of both processes occur in the same patient. Furthermore, uric acid levels may vary in the same
individual by as much as 1 to 2 mg per dL during the course of a day, due to the effects of diet and exercise.

Genetic mechanisms mediating hyperuricemia include overproduction due to mutations of two enzymes: hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and phosphoribosyl pyrophosphate synthetase (PRPPS) (Table 61.1). Subjects with Lesch-Nyhan syndrome (due to a mutation of HGPRT on the X chromosome) present in childhood with neurologic manifestations (mental retardation, choreoathetosis, and dystonia) and have an increased risk for nephrolithiasis, renal failure, and gout. A partial deficiency of HGPRT may manifest later in life as recurrent gout and/or nephrolithiasis (partial HGPRT deficiency (Kelley-Seegmiller syndrome).³⁰ Other genetic mechanisms include subjects with the uromodulin mutation, who develop hyperuricemia (due to underexcretion) with early and progressive renal disease (see subsequent text). Certain populations such as indigenous peoples living in Oceania also have higher uric acid levels than Caucasian populations.³¹ Finally, African Americans also have higher uric acid levels and a twofold higher incidence of gout compared to Caucasian or Asian populations³²; however, this could also reflect diets higher in fructose-containing sugars (see subsequent text) rather than genetic mechanisms.

TABLE 61.1 Major Causes of Hyperuricemia

Genetic causes
	Familial hyperuricemic nephropathy (mutation of uromodulin)
	Lesch-Nyhan syndrome (HGPRT mutation)
	Phosphoribosyl pyrophosphate synthetase mutation (PRPPS)
Dietary causes
	Diet high in purines (organ meats, shellfish, fatty meats)
	Diet high in fructose (high fructose corn syrup, table sugar, honey)
	Ethanol
	Low salt diet
Drugs
	Thiazides
	Loop diuretics
	Calcineurin inhibitors (cyclosporine > tacrolimus)
	Pyrazinamide
	Low dose aspirin
Volume depletion
Hypoxia (systemic or tissue)
Increased cell turnover (myeloproliferative disorders, polycythemia vera)
Conditions associated with higher uric acid levels
Renal failure
Obesity metabolic syndrome
Untreated hypertension
African-American race
Preeclampsia
Vigorous exercise

Hyperuricemia may also result from diets high in purines, from ethanol, and from fructose. The effect of alcohol is in part related to increased urate synthesis, which is due to enhanced turnover of ATP during the conversion of acetate to acetyl-CoA as part of the metabolism of ethanol.³³ In addition, acute alcohol consumption causes lactate production, and because lactate is an antiuricosuric agent, it will reduce renal urate excretion and exacerbate hyperuricemia.³⁴ Fructose (a simple sugar present in sucrose, table sugar, high fructose corn syrup, honey, and fruits) can also induce a rapid rise in serum uric acid, due in part to its rapid phosphorylation in hepatocytes with the stimulation of AMP deaminase and ATP consumption.³⁵ Chronic fructose consumption also stimulates uric acid synthesis.³⁵ It has been proposed that the marked increase in fructose intake may have a role in the rising levels of serum uric acid and obesity worldwide.³⁶

Uric acid may also be affected by exercise, with moderate exercise reducing urate levels (probably by increasing renal blood flow) and severe exercise causing a rise in uric acid (probably due to ATP consumption with adenosine and xanthine formation). Urate levels vary among gender, in that premenopausal women have lower uric acid, a fact attributed to the uricosuric effect of estrogen.³⁷ The mechanism may relate to gender effects on URAT-1 expression, as recent studies suggest that male mice have higher URAT-1 expression in their proximal tubules compared to female mice.³⁸ Androgens also increase xanthine oxidase levels that might contribute to the higher uric acid levels observed in men.³⁹ Uric acid also tends to increase in the setting of low blood volume and/or low salt diet (due to increased proximal reabsorption), and following the administration of catecholamines or angiotensin II (due to renal vasoconstriction resulting in increased reabsorption). Urate production also relates to body size and weight, so that larger persons produce more urate than those who are smaller. Hyperuricemia is particularly common in the obesity and metabolic syndrome (thought to be secondary to the effect of insulin to stimulate uric acid reabsorption)⁴⁰ and in untreated hypertension (thought to be due to reduced renal blood flow).⁴¹ Thiazides also increase uric acid reabsorption by decreasing blood volume and via direct interaction with the organic anion exchanger.

Other drugs (cyclosporine, pyrazinamide, low dose aspirin) also increase uric acid, primarily by interfering with renal excretion. In addition, the generation of organic anions such as lactate, β-hydroxybutyrate, and others may interfere with urate secretion in the proximal tubule and cause a rise in serum uric acid. Chronic lead ingestion can also cause hyperuricemia by reducing urate excretion, whereas high concentrations tend to cause proximal tubular injury with no rise in uric acid.

Uric acid is also increased in the setting of tissue hypoxia⁴² or with cell turnover.⁴³ With tissue hypoxia, ATP is consumed
and the isoform, xanthine oxidase, is induced, resulting in increased local uric acid concentrations. Uric acid levels are thus high in subjects with congestive heart failure, high altitude hypoxia, congenital cyanotic heart disease, and with obstructive sleep apnea. Uric acid levels are commonly elevated with certain malignancies, especially leukemias and lymphomas, and levels may sharply rise following chemotherapy (see acute urate nephropathy in the following text).⁴⁴ Finally, uric acid has a tendency to be elevated in polycythemia vera and other myeloproliferative disorders.⁴⁵

In the setting of reduced renal function, the fractional excretion of urate increases but is not enough to fully compensate for the reduction in glomerular filtration rate (GFR), and as a consequence serum uric acid levels rise. Conversely, uric acid excretion via the gastrointestinal tract is also enhanced,⁴⁶ and therefore serum uric acid levels tend to be only mildly elevated in patients with chronic renal disease, and gout is relatively rare.

Low uric acid levels (levels <2.0 mg per dL) can occur via a variety of mechanisms, including with liver disease (due to decreased production), Fanconi syndrome (due to impaired proximal tubular function), and with diabetic glycosuria (due to proximal tubular dysfunction) (Table 61.2). Drugs such as probenecid, high-dose salicylates, sulfinpyrazone, benziodarone, benzbromarone, and losartan are all uricosuric, whereas allopurinol, febuxostat, and oxypurinol lower uric acid by blocking xanthine oxidase. Statins also lower uric acid,⁴⁷ and recombinant uricase (rasburicase) can markedly reduce serum uric acid and is approved for use in children with tumor lysis syndrome (in which marked hyperuricemia may develop).⁴⁸ There is also a hereditary hypouricemia syndrome that has been observed, and is particularly common in Japan, where it has been shown to be due to a mutation in the URAT-1 gene.⁴⁹ A similar hypouricemia syndrome has also been observed with mutations in SLC2A9.⁵⁰ These patients are particularly prone to develop acute renal failure following vigorous exercise, in which it is postulated to be due to massive uricosuria following ATP consumption in the muscle.

FIGURE 61.3 Pathology of acute uric acid nephropathy. A: Yellow/white streaks in the pyramids represent intratubular urate deposition (arrows). B: Intratubular urate deposition (Schultz stain, ×6). C: Urate precipitation in ducts of renal medulla with a denuded tubular basement membrane (arrows, H&E, × 125). (From Nickeleit V, Mihatsch MJ. Uric acid nephropathy and end-stage renal disease—review of a non-disease. Nephrol Dial Transplant. 1997;12(9):1832-1838.) (See Color Plate.)

TABLE 61.2 Major Causes of Hypouricemia

Liver disease

Fanconi syndrome

Diabetes (with glycosuria)

Inappropriate secretion of vasopressin

Familial hypouricemia (due to URAT1 mutation)

Total parenteral hyperalimentation

Medications with uricosuric property including aspirin (>2.0 g/day), X-ray contrast materials, ascorbic acid, calcitonin, outdated tetracycline, and glyceryl guaiacolate

URIC ACID AND RENAL DISEASE

In the following section, we discuss the major associations of uric acid with renal disease.

Acute Kidney Injury Associated with Hyperuricemia

Acute urate nephropathy is a form of acute renal failure that may occur when serum uric acid rapidly rises, such as in patients with malignancies following chemotherapy (“tumor lysis” syndrome).⁴⁴ Typically the patient has a hematologic malignancy in which rapid tumor lysis occurs, resulting in the release of DNA and RNA and their rapid metabolism to uric acid by the liver and other tissues. Serum uric acid levels may increase to greater than 14 mg per dL (>840 µM), resulting in a marked increase in urinary urate excretion that exceeds its solubility. Uric acid crystals form within the tubules, leading to obstruction and sometimes rupturing into the interstitium (Fig. 61.3). Monocytes and T cells are attracted to the site, and form giant cell reactions with tubular
proliferation and extracellular matrix deposition.⁵¹ Diagnosis is facilitated by the characteristic clinical syndrome and with a urinary uric acid/urinary creatinine ratio of > 1 mg per mg (or >0.66 mM/mM),⁵² and by the presence of urate crystals in the urinary sediment. Historically, treatment consisted of forced alkaline diuresis (to facilitate solubilizing the urate) and large doses of xanthine oxidase inhibitors (typically allopurinol 300 to 600 mg per day). Recently, recombinant uricase (rasburicase) has become available, which can be administered intravenously and effectively lowers serum uric acid levels and corrects renal dysfunction more rapidly than allopurinol.⁴⁸ Dialysis can also be used to acutely lower the serum uric acid levels. The natural course is one similar to that for acute renal failure of any etiology with a period of oliguria, followed by partial or complete clinical recovery. However, some degree of residual renal injury/damage is common.

Hyperuricemia may also act as an independent risk factor for acute kidney injury in other settings such as following cardiovascular surgery or in association with the administration of nephrotoxic agents such as contrast or cisplatin.⁵³,⁵⁴ Experimentally raising uric acid has also been shown to exacerbate acute kidney injury from cisplatin.⁵⁵ The mechanism is not due to crystals but rather appears to be secondary to the induction of local inflammation by uric acid. These observations have led to renewed interest that uric acid may be a potentially modifiable risk factor for preventing acute kidney injury.

FIGURE 61.4 Pathology of chronic uric acid nephropathy. A: Gout tophi in renal pyramid (arrow) representing fibrosis and urate deposit. B: Typical gouty tophus in renal medulla surrounded by mononuclear inflammatory cells and giant cells (arrow, H&E, × 160). (From Nickeleit V, Mihatsch MJ. Uric acid nephropathy and end-stage renal disease—review of a non-disease. Nephrol Dial Transplant . 1997;12(9):1832-1838.)

Hyperuricemia as a Primary Cause of Chronic Kidney Disease

Hyperuricemia is common in subjects with chronic kidney disease. Some cases are due to specific entities, such as lead nephropathy or familial juvenile hyperuricemic nephropathy (discussed later). Uric acid is also retained with a reduction in GFR, so in many cases the rise in uric acid is likely secondary to chronic kidney disease (CKD). However, there remains the possibility that the uric acid may still have a role in modifying progression of renal disease.

Originally the entity of “gouty nephropathy” was attributed to the progressive renal disease seen commonly in subjects with gout. Natural history studies prior to the availability of uric acid-lowering drugs reported that as much as 25% of gouty subjects developed proteinuria, 50% developed renal insufficiency, and 10% to 25% developed end-stage renal disease (ESRD).⁵²,⁵⁶ Histologic changes consist of arteriolosclerosis, glomerulosclerosis, and tubulointerstitial fibrosis, similar to the findings one observes in patients with hypertensive renal disease (nephrosclerosis) or with aging (Fig. 61.4).⁵⁶,⁵⁷ In addition, subjects with chronic gout often have focal deposition of monosodium urate in interstitial areas, especially the outer
medulla. Although intrarenal crystal deposition was originally thought to be mediating the renal injury,⁵⁷ this was later dispelled due to the focal deposition of crystals despite diffuse disease⁵⁸ and the fact that the renal disease was commonly associated with hypertension or aging, both conditions associated with the development of microvascular disease, glomerulosclerosis, and tubulointerstitial fibrosis.⁵⁹,⁶⁰,⁶¹ Finally, although some studies suggested that lowering uric acid could improve the renal disease in gout,⁶²,⁶³ other studies could not demonstrate any significant improvement of renal function with allopurinol.⁶⁴ Therefore, many authorities considered the term “gouty nephropathy” a misnomer, and concluded that uric acid had little to do with the renal disease present in these subjects.⁶⁵

New Insights on the Entity of Primary Hyperuricemic Nephropathy

Renewed interest on the role of gout and/or asymptomatic hyperuricemia in CKD was sparked by the recognition that it seemed inappropriate to use the presence of hypertension to explain every case of renal insufficiency in the gouty patient, because most subjects with essential hypertension have relatively preserved renal function.⁶⁶ Another implicit assumption was that gouty nephropathy had to be due to crystal deposition, and the possibility that uric acid might mediate effects through crystal-independent mechanisms was not considered. Furthermore, the analysis also assumed that the presence of hypertension was a separate cause of renal disease and that it had to be independent of the uric acid. This led to a proposal to reinvestigate the role of uric acid in chronic renal disease.⁶⁶

Subsequently numerous epidemiologic studies have shown that serum uric acid is an independent risk factor for developing CKD. In one Japanese study, hyperuricemia conferred a 10.8-fold increased risk in women and a 3.8-fold increased risk in men for the development of CKD compared to those with normal uric acid levels.⁶⁷ This higher relative risk in subjects with hyperuricemia was independent of age, body mass index, systolic blood pressure, total cholesterol, serum albumin, glucose, smoking, alcohol use, exercise habits, proteinuria, and hematuria. An elevated uric acid was also independently associated with a markedly increased risk of renal failure in another study of more than 49,000 male railroad workers.⁶⁸ A second insight came from experimental studies in which chronic mild hyperuricemia was induced in rats.⁶⁹,⁷⁰ Because rats have functional uricase, the model of hyperuricemia was induced by administering the uricase inhibitor, oxonic acid, to the diet.⁶⁹,⁷⁰ This resulted in serum uric acid levels that were only 1.5- to 3.0-fold greater than in the normal rat, levels which did not result in intratubular or interstitial urate crystal deposition. Over time, however, rats developed hypertension and progressive renal disease. Early in the course the rats developed arteriolar thickening and rarely hyalinosis of the preglomerular arterioles, often accompanied by glomerular hypertrophy.⁷⁰,⁷¹ Proteinuria appeared subsequently with the development of worsening vascular disease, glomerulosclerosis, and interstitial fibrosis.⁷⁰ The lesion was identical to that observed with nephrosclerosis of hypertension, with aging-associated glomerulosclerosis, and with gouty nephropathy, except for the absence of crystal deposition that had been observed in the latter condition. This led the authors to suggest that chronic hyperuricemia may cause renal disease and hypertension via a crystal-independent pathway.

Further studies showed that uric acid was able to induce endothelial dysfunction in vitro, and that it could inhibit endothelial release of nitric oxide, block endothelial cell proliferation, and induce senescence via an activation of the local renin-angiotensin system and an induction of oxidative stress.⁷²,⁷³,⁷⁴ Uric acid also stimulated vascular smooth muscle cell proliferation via uptake of urate into the cell with activation of MAP kinases, nuclear transcription factors (including NF-κB and AP-1), and inflammatory mediators (including monocyte chemoattractant protein-1 and C-reactive protein).⁷¹,⁷²,⁷³

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