Uric Acid Transport Research Articles

Hypouricaemia and acute kidney injury: a hereditary condition should be considered.

I read with interest the case report by Tadokoro et al.1 about a 17-year-old woman, presumably of Japanese ethnicity, who presented with acute kidney injury (AKI) following a basketball game. In view of the clinical course and computed tomography images, a diagnosis of exercise-induced acute kidney injury (EIAKI) was made; notably, uric acid (UA) was 1.3 mg/dl on admission. Although the association of EIAKI with hypouricaemia (by convention defined as a serum urate concentration of <2 mg/dl)2 was duly acknowledged, I was surprised that the authors did not elaborate on the potential causes of this finding. A UA level of 1.3 mg/dl in the context of AKI is highly unusual and should alert the clinician to the possibility of an underlying defect in renal UA reabsorption. Specifically, renal hypouricaemia (RHUC), a genetically heterogenous disorder caused by mutations in two major renal tubular UA transporters (URAT1, encoded by SLC22A12, and GLUT9, encoded by SLC2A9), predisposes affected individuals to kidney stones and recurrent AKI, the latter typically provoked by exercise.3 Although certainly qualifying as an orphan disease, the prevalence of RHUC varies significantly and is reasonably common in certain Asian regions, particularly in Japan, where the estimated prevalence reaches 0.5% in the general population.4 The pathophysiology of EIAKI is incompletely understood. UA is a powerful antioxidant and hypouricaemia may trigger an oxidative imbalance during exercise; resultant renovascular spasm shares similarities with ischaemia-reperfusion injury.2,3

Glucose Transporter 9 (GLUT9) Plays an Important Role in the Placental Uric Acid Transport System.

Background: Hyperuricemia is a common laboratory finding in pregnant women compromised by preeclampsia. A growing body of evidence suggests that uric acid is involved in the pathogenesis of preeclampsia. Glucose transporter 9 (GLUT9) is a high-capacity uric acid transporter. The aim of this study was to investigate the placental uric acid transport system, and to identify the (sub-) cellular localization of GLUT9. Methods: Specific antibodies against GLUT9a and GLUT9b isoforms were raised, and human villous (placental) tissue was immunohistochemically stained. A systemic GLUT9 knockout (G9KO) mouse model was used to assess the placental uric acid transport capacity by measurements of uric acid serum levels in the fetal and maternal circulation. Results: GLUT9a and GLUT9b co-localized with the villous (apical) membrane, but not with the basal membrane, of the syncytiotrophoblast. Fetal and maternal uric acid serum levels were closely correlated. G9KO fetuses showed substantially higher uric acid serum concentrations than their mothers. Conclusions: These findings demonstrate that the placenta efficiently maintains uric acid homeostasis, and that GLUT9 plays a key role in the placental uric acid transport system, at least in this murine model. Further studies investigating the role of the placental uric acid transport system in preeclampsia are eagerly needed.

Identification of novel dual inhibitors targeting XOR and URAT1 via multiple virtual screening methods

The clinically applicable single uric acid transporter 1 (URAT1) inhibitor or xanthine oxidoreductase (XOR) inhibitor cannot solve the clinical needs in anti-hyperuricemia well. It is expected that combined inhibition of both XOR and URAT1 might effectively decrease the level of uric acid and avoid the issue of insufficient potency by single-target drugs. 3D-QSAR pharmacophore modeling, molecular docking, and ADMET filtering were applied for potential dual inhibitors. And top-ranked three compounds were selected to MD simulation analysis, with utilization of binding free energy and decomposition data. 4917-2281, 4109-2078 and C301-8913, have potential inhibitory potency for both XOR and URAT1 and were suitable for further experimental analysis and modification.

Impact of hyperuricemia on chronic kidney disease and atherosclerotic cardiovascular disease.

Hyperuricemia is caused by reduced renal/extrarenal excretion and overproduction of uric acid. It is affected by genetic predisposition related to uric acid transporters and by visceral fat accumulation due to overnutrition. The typical symptomatic complication of hyperuricemia is gout caused by monosodium urate crystals. Accumulated evidence from epidemiological studies suggests that hyperuricemia is also a risk factor for hypertension, chronic kidney disease (CKD) and atherosclerotic cardiovascular disease (CVD). However, it remains to be determined whether urate-lowering therapy for asymptomatic patients with hyperuricemia is effective in preventing CKD or CVD progression. This mini review focuses mainly on recent papers investigating the relationship between hyperuricemia and CKD or CVD and studies of urate-lowering therapy. Accumulated studies have proposed mechanisms of renal damage and atherosclerosis in hyperuricemia, including inflammasome activation, decreased nitric oxide bioavailability and oxidative stress induced by uric acid, urate crystals and xanthine oxidoreductase (XOR)-mediated reactive oxygen species. Since patients with hyperuricemia are a heterogeneous population with complex pathologies, it may be important to assess whether an outcome is the result of decreasing serum uric acid levels or an inhibitory effect on XOR. To clarify the impact of hyperuricemia on CKD and CVD progression, high-quality and detailed clinical and basic science studies of hyperuricemia and purine metabolism are needed.

高尿酸血症・痛風の治療ガイドラインと尿酸トランスポーター関連薬剤の概要

Uric acid (UA) transporters, including urate transporter 1 (URAT1), glucose transporter 9 (GLUT9), and ATP-binding cassette subfamily G member 2 (ABCG2), are involved in hyperuricemia. A novel selective urate reabsorption inhibitor, developed in Japan, reduces serum UA levels by selectively inhibiting URAT1. The Japanese Society of Gout and Nucleic Acid Metabolism published "Guidelines for the Management of Hyperuricemia and Gout (3rd edition, 2022-Supplementary Edition-)" in March 2022. This guideline provides valuable information for decision-making in clinical management of hyperuricemia.

Anserine beneficial effects in hyperuricemic rats by inhibiting XOD, regulating uric acid transporter and repairing hepatorenal injury.

This study aims to investigate the anti-hyperuricemia effect and mechanism of anserine in hyperuricemic rats. Hyperuricemic rats were induced with a combination of 750 mg per kg bw d potassium oxazinate (PO) and 200 mg per kg bw d hypoxanthine for a week, and the rats were separately orally administered anserine (20, 40, 80 mg kg-1) and allopurinol (10 mg kg-1) for three weeks. The results show that the content of serum uric acid (SUA) decreased by approximately 40% and 60% after the intervention of anserine and allopurinol, respectively. The activity of superoxide dismutase (SOD) was increased and the levels of malondialdehyde (MDA), alkaline phosphatase (ALP) and alanine aminotransferase (ALT) were significantly decreased in the anserine groups. After the administration of anserine, the contents of blood urea nitrogen (BUN) and creatinine (Cr) were reduced in the kidney, and the levels of the proinflammatory cytokines IL-1β, IL-6β, TNF-α and TGF-β and inflammatory cell infiltration were reduced in both the liver and kidney. Moreover, the gene expressions of xanthine oxidase (XOD), renal urate transporter 1 (URAT1) and glucose transporter type 9 (GLUT9) were downregulated by anserine administration, and the gene expressions of ATP-binding cassette transporter G2 (ABCG2), organic anion transporter 1 (OAT1) and organic anion transporter 3 (OAT3) were upregulated at the same time. These findings suggest that hepatorenal injury was repaired by anserine, which further regulated the expression of hepatic XOD and renal URAT1, GLUT9, ABCG2, OAT1 and OAT3 to relieve hyperuricemia in rats.

NRBP1 modulates uric acid transporter ABCG2 expression by activating the Wnt/β-catenin pathway in HK-2 cells

BackgroundNuclear receptor binding protein 1 (NRBP1) and ATP-binding cassette subfamily G member 2 (ABCG2) was the gout risk gene and high-capacity urate exporter respectively. However, the relationship between NRBP1 and ABCG2 and the underlying molecular mechanism contributing to these associations are unknown. MethodsFirstly, the efficiency of the overexpression and knockdown of NRBP1 was confirmed by western blot. Next, the effect of NRBP1 overexpression and knockdown on the expression of ABCG2, organic anion transporter 1 (OAT1), glucose transporter 9 (GLUT9) and urate transporter 1 (URAT1) was detected by qRT-PCR and western blot. At the same time, the cellular location of ABCG2 and its expression after NRBP1 overexpression and knockdown was tested by immunofluorescence (IF) staining. Then, the mechanism of NRBP1 modulates ABCG2 expression was evaluated by western blot with or without the β-catenin inhibitor (21H7). ResultsThe lentivirus system was used to generate stable NRBP1 overexpression, while the plasmids carrying a NRBP1 siRNA was generated to knockdown NRBP1 expression in HK-2 cells. Meanwhile, the overexpression of NRBP1 significantly decreased the mRNAs and proteins expression of GLUT9 and URAT1, while the knockdown of NRBP1 increased the mRNAs and proteins expression of ABCG2 significantly. In addition, the NRBP1 modulates the expression of ABCG2 was by ctivating the Wnt/β-catenin pathway in HK-2 cells according to the IF and western blot results. ConclusionTaken together, our study demonstrated that NRBP1 inhibition played an essential role in attenuating hyperuricemia and gout by upregulation of ABCG2 via Wnt/β-catenin signaling pathway in HK-2 cells.

Enterocyte synthesizes and secrets uric acid as antioxidant to protect against oxidative stress via the involvement of Nrf pathway

The gut is an important site to excreting uric acid (UA) in addition to the kidney. The gastrointestinal tract is constantly exposed to various potentially harmful substances, triggering intestinal oxidative damage. In the present study, the hypothesis that UA is can be synthesized to function as an antioxidant in the gut is evaluated. The synthesis and secretion of UA by enterocytes were analyzed in the presence of inosine, a precursor of UA, febuxostat (Fx), an inhibitor of xanthine oxidase (XOR), and H2O2. The regulation of Nrf2 pathway on UA secretion and transport were evaluated in the present of agonist (TBHQ) and inhibitor (ML385) of Nrf2. The in vivo result showed that UA and its oxidation product allantoin were presented in gut contents along the gastrointestinal tract and the highest level of UA and allantoin were detected in duodenum and jejunum respectively. The genes in the de novo purine nucleotide synthesis and salvage-catabolism pathways, and UA transporters were expressed in the intestinal tract. In the in vitro cultured enterocytes and everted gut sacs, inosine stimulated UA synthesis and secretion. H2O2 stimulated UA synthesis and secretion and meanwhile induced oxidative damage. UA attenuated H2O2-induced oxidative damage by Nrf2 pathway. UA secretion and transport were reduced by blocking Nrf2 with ML385, while increased by activating Nrf2 with TBHQ. This study provides new insights into the antioxidant effects if UA on intestinal lumen. The result suggests that activation of Nrf2 pathway is involved in the transportation and secretion of UA.

Metagenome-genome-wide association studies reveal human genetic impact on the oral microbiome

The oral microbiota contains billions of microbial cells, which could contribute to diseases in many body sites. Challenged by eating, drinking, and dental hygiene on a daily basis, the oral microbiota is regarded as highly dynamic. Here, we report significant human genomic associations with the oral metagenome from more than 1915 individuals, for both the tongue dorsum (n = 2017) and saliva (n = 1915). We identified five genetic loci associated with oral microbiota at study-wide significance (p < 3.16 × 10−11). Four of the five associations were well replicated in an independent cohort of 1439 individuals: rs1196764 at APPL2 with Prevotella jejuni, Oribacterium uSGB 3339 and Solobacterium uSGB 315; rs3775944 at the serum uric acid transporter SLC2A9 with Oribacterium uSGB 1215, Oribacterium uSGB 489 and Lachnoanaerobaculum umeaense; rs4911713 near OR11H1 with species F0422 uSGB 392; and rs36186689 at LOC105371703 with Eggerthia. Further analyses confirmed 84% (386/455 for tongue dorsum) and 85% (391/466 for saliva) of host genome-microbiome associations including six genome-wide significant associations mutually validated between the two niches. As many of the oral microbiome-associated genetic variants lie near miRNA genes, we tentatively validated the potential of host miRNAs to modulate the growth of specific oral bacteria. Human genetics accounted for at least 10% of oral microbiome compositions between individuals. Machine learning models showed that polygenetic risk scores dominated over oral microbiome in predicting risk of dental diseases such as dental calculus and gingival bleeding. These findings indicate that human genetic differences are one explanation for a stable or recurrent oral microbiome in each individual.

Increased Lung Uric Acid Deteriorates Pulmonary Arterial Hypertension.

BackgroundRecent studies have demonstrated that uric acid (UA) enhances arginase activity, resulting in decreased NO in endothelial cells. However, the role of lung UA in pulmonary arterial hypertension (PAH) remains uncertain. We hypothesized that increased lung UA level contributes to the progression of PAH.Methods and ResultsIn cultured human pulmonary arterial endothelial cells, voltage‐driven urate transporter 1 (URATv1) gene expression was detected, and treatment with UA increased arginase activity. In perfused lung preparations of VEGF receptor blocker (SU5416)/hypoxia/normoxia‐induced PAH model rats, addition of UA induced a greater pressure response than that seen in the control and decreased lung cGMP level. UA‐induced pressor responses were abolished by benzbromarone, a UA transporter inhibitor, or L‐norvaline, an arginase inhibitor. In PAH model rats, induction of hyperuricemia by administering 2% oxonic acid significantly increased lung UA level and induced greater elevation of right ventricular systolic pressure with exacerbation of occlusive neointimal lesions in small pulmonary arteries, compared with nonhyperuricemic PAH rats. Administration of benzbromarone to hyperuricemic PAH rats significantly reduced lung UA levels without changing XOR (xanthine oxidoreductase) activity, and attenuated right ventricular systolic pressure increase and occlusive lesion development. Topiroxostat, a XOR inhibitor, significantly reduced lung XOR activity in PAH rats, with no effects on increase in right ventricular systolic pressure, arterial elastance, and occlusive lesions. XOR‐knockout had no effects on right ventricular systolic pressure increase and arteriolar muscularization in hypoxia‐exposed mice.ConclusionsIncreased lung UA per se deteriorated PAH, whereas XOR had little impact. The mechanism of increased lung UA may be a novel therapeutic target for PAH complicated with hyperuricemia.

Screening of bioactivity-oriented extraction approach and quality control standards of lotus leaf extracts with dual functions

In the present study, various lotus leaf extracts were prepared by multiple methods, characterized by 12 alkaloids, 14 flavonoids, and superoxide anion radical scavenging (OS) and xanthine oxidase inhibitory (XOI) activities, and divided into 3/4 groups with different characteristics. Both alkaloids and flavonoids contributed to XOI activity of representative lotus leaf extract. Norcoclaurine, O-nornuciferine, N-nornuciferine, nuciferine, luteolin, diosmetin, quercetin, and quercetin-3-O-glucuronide were defined as quality control standards for lotus leaf extracts with dual OS and XOI activities. Enzymatic hydrolysis coupled with ultrasound-assisted extraction method using 50% (v/v) ethanol was the most favorable approach for preparing food-grade lotus leaf extract with dual functions. Network pharmacology revealed that this extract having abundant alkaloids and flavonoids (especially flavonoid aglycones) could improve hyperuricemia by multiple actions on uric acid synthesis and transport, inflammation response, oxidative stress and lipid metabolism. Our study provided crucial data about clear quality control standards for plant-based functional food with potential hypouricemic effect.

Eurycomanol alleviates hyperuricemia by promoting uric acid excretion and reducing purine synthesis

BackgroundAn elevated level of blood uric acid (UA) leads to serious damages to human health. In clinic, xanthine oxidase inhibitor is commonly used to reduce uric acid production. However, UA excretion promotion drug is rare. Our previous study demonstrated that the 70% ethanolic extract of stem of Eurycoma longifolia could effectively increase UA excretion and decrease blood level of UA in hyperuricemia animal model. In this paper, we tried to find active substance on UA regulation from E. longifolia. MethodsThe constituents of stem from E. longifolia were isolated and analyzed by chemical and spectral methods. Ultra Performance Liquid Chromatography was applied to measure the concentrations of UA in serum and urine. H&E staining was used to characterize renal histopathological changes. The protein and mRNA expressions of UA transporters were measured by western blot and quantitative real-time PCR analysis. ResultsTen kinds of quassinoids were isolated from stem of E. longifolia, and the structures were identified. Pharmacological research revealed the major component, eurycomanol (5–20 mg/kg, p.o.) significantly decreased serum UA level and increased 24 h clearance of uric acid in potassium oxonate and adenine induced hyperuricemic mice. Eurycomanol ameliorated UA induced kidney histological injury, inhibited hepatic purine synthesis through decreasing phosphoribosyl pyrophosphate synthetase, promoted UA excretion by modulation of renal and intestinal urate transporters, such as GLUT9, ABCG2, OAT1, and NPT1. ConclusionThe results showed eurycomanol from E. longifolia can promote UA excretion through kidney and intestine, decrease hepatic purine synthesis and further keep UA homeostasis, suggesting that eurycomanol has the potential to be developed into a novel drug for the treatment of under-excretion type hyperuricemia.

Analysis of Lesunirad in Rat Plasma with an Improved Sensitivity by CZE-MS/MS Detection: Application to Pharma- cokinetic Study

Lesunirad is an uricosuric drug that inhibits the uric acid transporter-1 (URAT-1) and organic anion transporter-4 within the proximal renal tubule, which are involved in acid reabsorption within the kidney 1. In this article, a new CZE coupled with electron-spray ionization - tandem MS approach has been employed for lesunirad in rat plasma after precipitation of plasma proteins by acetonitrile using internal standard, loratadine. By one step-deproteinization approach, plasma sample was set using 0.3 mL of acetonitrile mixed with 0.3 mL plasma specimen. Electrophoretic segregation and detection of lesunirad from plasma samples were achieved by using fused silica capillary made up of sheath liquid (SL) composition of water consisting of 0.25 % of formic acid and methanol in the ratio of 40:60 and BGE containing 25 mM of ammonium formate buffer solution, injected at a rate of flow of 0.3 nL/min. Thereafter, analytes were monitored using ESI with positive ion MRM and was applied for the evaluation of the precursor to product ion at m/z 406 → 221 for lesinurad and m/z 383 → 337 for IS loratadine. The method showed better linearity in the range of 10-1000 ng/mL and was authenticated as stated by the current ICH regulations and the results obtained were within the acceptable limits. Due to high sensitivity, less time consuming and sample volume requirement, finally, the CZE-MS was effectively applicable to pharmacokinetic studies of lesunirad in rats and the concentration-time profile of CZE-MS in rat plasma sample was found to correlate well when compared to UHPLC-MS/MS assay available in the literature.

The anti-hyperuricemic effects of green alga Enteromorpha prolifera polysaccharide via regulation of the uric acid transporters in vivo

A novel polysaccharide obtained from Enteromorpha prolifera (EPP) was purified through diethylaminoethyl cellulose-52 and Sephadex G-75 chromatography. Fourier transform infrared spectroscopy, high-performance liquid chromatography, and nuclear magnetic resonance (NMR) spectroscopy were employed to analyse the structure of EPP. It mainly comprised rhamnose, glucuronic acid, galactose, arabinose, and xylose at a molar ratio of 20.45:12.74:10.99:5.84:1.95, and its average molecular weight was 46.56 kDa. The seven major glycosidic residues identified by NMR were as follows: →2)-α-L-Araf-(1→, →2)-α-L-Rhap-(1→, →4)-α-L-Rhap-(1→, →2,6)-β-D-Galp-(1→, →4)-β-D-GlcpA-(1→, →3,4)-β-D-GlcpA-(1→, and →4)-β-Xylp-(1→. The effect of EPP on hyperuricemic mice was determined by analysing correlative general physical parameters, renal histopathology, renal gene expressions, and gut microbiome. EPP significantly reduced serum uric acid (UA), serum blood urea nitrogen, serum xanthine oxidase (XOD), and hepatic XOD as well as improved histological parameters in hyperuricemic mice. Furthermore, mRNA and protein expression analyses showed the upregulation of UA excretion genes such as ABCG2, OAT1, and NPT1 and downregulation of UA resorption gene URAT1. Moreover, EPP maintained the stability of the intestinal flora and confirmed that Parasutterella is closely related to the regulation of hyperuricemia. This study is the first to demonstrate the anti-hyperuricemic activity of EPP and highlight its therapeutic potential for hyperuricemia-related diseases.

Characterization of a Compound Heterozygous SLC2A9 Mutation That Causes Hypouricemia.

Renal hypouricemia is a rare genetic disorder. Hypouricemia can present as renal stones or exercise-induced acute renal failure, but most cases are asymptomatic. Our previous study showed that two recessive variants of SLC22A12 (p.Trp258*, pArg90His) were identified in 90% of the hypouricemia patients from two independent cohorts: the Korean genome and epidemiology study (KoGES) and the Korean Cancer Prevention Study (KCPS-II). In this work, we investigate the genetic causes of hypouricemia in the rest of the 10% of unsolved cases. We found a novel non-synonymous mutation of SLC2A9 (voltage-sensitive uric acid transporter) in the whole-exome sequencing (WES) results. Molecular dynamics prediction suggests that the novel mutation p.Met126Val in SLCA9b (p.Met155Val in SLC2A9a) hinders uric acid transport through a defect of the outward open geometry. Molecular analysis using Xenopus oocytes confirmed that the p.Met126Val mutation significantly reduced uric acid transport but does not affect the SLC2A9 protein expression level. Our results will shed light on a better understanding of SLC2A9-mediated uric acid transport and the development of a uric acid-lowering agent.

Dapagliflozin and xanthine oxidase inhibitors improve insulin resistance and modulate renal glucose and urate transport in metabolic syndrome.

Disturbance in glucose and uric acid metabolism is the major disorder of metabolic syndrome (MetS). The kidneys play an important role in the management of glucose and uric acid. The aim of our study was to investigate alterations in renal glucose and uric acid transporters in animals with MetS after treatment with dapagliflozin and xanthine oxidase inhibitors (allopurinol and febuxostat). Sprague-Dawley rats were fed normal chow or a high fructose diet for the first 3months. The fructose-fed animals were then treated with dapagliflozin, allopurinol, febuxostat, or no treatment for the next 3months. Fasting glucose, insulin resistance, and hyperuricaemia were improved in all treatment groups except that in the fructose group (all p<0.05). Both allopurinol and febuxostat reversed the increase in levels of sodium glucose cotransporter (SGLT) 1, SGLT2, and glucose transporter (GLUT) 2 (all p<0.05). Dapagliflozin alleviated hyperuricaemia and induced uricosuria without affecting serum xanthine oxidase activity. Dapagliflozin suppressed the expression of GLUT9, urate transporter, and urate anion exchanger 1 (all p<0.05), which was similar to the effects of allopurinol and febuxostat. The results suggest that treatment with dapagliflozin and xanthine oxidase inhibitors improved insulin resistance and reversed the increased expression of glucose and urate transporters in the kidney.

Diclofenac toxicity in susceptible bird species results from a combination of reduced glomerular filtration and plasma flow with subsequent renal tubular necrosis.

Diclofenac caused the death of millions of vultures on the Asian subcontinent. Other non-steroidal anti-inflammatory drugs (NSAIDs) have since also been shown to be toxic to vultures with the exception of meloxicam. For this study, we evaluated the effect of diclofenac on renal uric acid transport and glomerulus filtration in an acute toxicity model. In a two-phase study with the same birds, healthy chickens (a validated model species) were treated intravenously with para-amino hippuric acid (PAH) and iohexol (IOH) in combination in phase 1. In phase 2, the same PAH and IOH combination was then combined with diclofenac (10 mg/kg). In both phases, blood and faeces were sequentially collected. In phase 1, the birds showed no signs of ill health. Moreover, PAH, IOH and uric acid clearance was rapid. In phase 2, two chickens showed early signs of hyperuricemia 8 hours after exposure and died approximately 24h later. Necropsy showed classic signs of renal damage and gout. Diclofenac had a rapid plasma half-life of elimination of less than 2 hours indicating that toxicity was likely due to an irreversible destruction of a physiological process. All the birds in phase 2 had decreased uric acid, PAH and IOH clearance in comparison to phase 1. The decrease in PAH clearance was variable between the birds (average of 71%) but was near 98% reduced in the two birds that died. It is concluded that diclofenac alters both renal perfusion and renal plasma flow, with death associated with tubular secretion being reduced to negligible functionality for a prolonged period. This would support previous in vitro findings of early cell death from ROS accumulation. However, further evaluation is needed to elucidate this final step.

The Extract of Sonneratia apetala Leaves and Branches Ameliorates Hyperuricemia in Mice by Regulating Renal Uric Acid Transporters and Suppressing the Activation of the JAK/STAT Signaling Pathway.

Sonneratia apetala Buch-Ham., an exotic mangrove species with antidiabetic, antibacterial, and antioxidant capacities, mainly distributes in the southeast coastal areas in China. The present work investigated the protective effects of Sonneratia apetala leaves and branches extraction (SAL) on hyperuricemia (HUA) in mice. Potassium oxonate (PO) and hypoxanthine (HX) were used to establish the HUA model by challenge for consecutive 7 days. Results revealed that SAL inhibited the increases in kidney weight and index compared to the vehicle group. Meanwhile, SAL significantly decreased the levels of uric acid (UA), creatinine (CRE), and blood urea nitrogen (BUN) in serum. Additionally, SAL inhibited the activity of xanthine oxidase (XOD) in the liver. SAL ameliorated PO- and HX-induced histopathological changes. Moreover, it regulated oxidative stress markers including malondialdehyde (MDA), catalase (CAT), superoxide dismutase (SOD) activity, and glutathione (GSH) content. Also, SAL inhibited the increases in renal levels of interleukin-6 (IL-6), interleukin-18 (IL-18), interleukin-1β (IL-1β), tumor necrosis factor (TNF-α), monocyte chemotactic protein 1 (MCP-1), and transforming growth factor-β (TGF-β). SAL remarkably reduced suppressor of cytokine signaling 3 (SOCS3), Janus kinase 2 (JAK2), and subsequent phosphorylation of signal transducer and activator of transcription 3 (STAT3) expression. In addition, SAL inhibited the activation of nuclear factor kappa-B (NF-κB) in the kidney. Furthermore, SAL protected against HUA by regulating renal UA transporters of organic anion transporter (OAT1), urate reabsorption transporter 1 (URAT1), and glucose transporter 9 (GLUT9). These findings suggested that SAL ameliorated HUA by inhibiting the production of uric acid and enhancing renal urate excretion, which are related to oxidative stress and inflammation, and the possible molecular mechanisms include its ability to inhibit the JAK/STAT signaling pathway. Thus, SAL might be developed into a promising agent for HUA treatments.

Mechanism of Traditional Medicine Tongfeng Li’an Granules on Hyperuricemic Rats Based on Regulating Uric Acid Transporter

Hyperuricemia (HUA) is a metabolic disorder of purine metabolism which leads to the increase of serum uric acid. Tongfeng Lian granule (TFLA) is a clinical empirical traditional herb prescription in China, is biobased natural product material. To study its regulatory mechanism on uric acid transporter in rats with HUA, the rat model of hyperuricemic was established by oral administration of potassium oxazinate (1.5 g/kg) and adenine (0.05 g/kg). The related indexes were detected to evaluate the uric Acid Transporter after treat with TFLA. In the results, compared with model group, the high dose TFLA can reduce the levels of Related serum biochemical indexes (*P &lt; 0.05, **P &lt; 0.01). TFLA could reduce the levels of URAT1, GLUT9 and increase the expression of OAT3 in kidney. In conclusion, TFLA can effectively inhibit the level of serum uric acid with hyperuricemia rats, and the possible mechanism related to TFLA inhibiting the reabsorption of uric acid by URAT1 and GLUT9, promoting the secretion of OAT3 and uric acid into urine.

Function of Uric Acid Transporters and Their Inhibitors in Hyperuricaemia.

Disorders of uric acid metabolism may be associated with pathological processes in many diseases, including diabetes mellitus, cardiovascular disease, and kidney disease. These diseases can further promote uric acid accumulation in the body, leading to a vicious cycle. Preliminary studies have proven many mechanisms such as oxidative stress, lipid metabolism disorders, and rennin angiotensin axis involving in the progression of hyperuricaemia-related diseases. However, there is still lack of effective clinical treatment for hyperuricaemia. According to previous research results, NPT1, NPT4, OAT1, OAT2, OAT3, OAT4, URAT1, GLUT9, ABCG2, PDZK1, these urate transports are closely related to serum uric acid level. Targeting at urate transporters and urate-lowering drugs can enhance our understanding of hyperuricaemia and hyperuricaemia-related diseases. This review may put forward essential references or cross references to be contributed to further elucidate traditional and novel urate-lowering drugs benefits as well as provides theoretical support for the scientific research on hyperuricemia and related diseases.