Uric Acid Transport Research Articles

Functional characterization of ENT2/SLC29A2 as a uric acid transporter

Functional characterization of ENT2/SLC29A2 as a uric acid transporter

Limosilactobacillus reuteri HCS02-001 Attenuates Hyperuricemia through Gut Microbiota-Dependent Regulation of Uric Acid Biosynthesis and Excretion.

Hyperuricemia is a prevalent metabolic disorder that arises from abnormal purine metabolism and reduced excretion of uric acid (UA). The gut microbiota plays a significant role in the biosynthesis and excretion of UA. Probiotics capable of purine degradation possess the potential to prevent hyperuricemia. Our study aimed to screen probiotics in areas with abundant dairy products and longevity populations in China, which could attenuate the level of UA and explore the underlying mechanism. In this study, twenty-three lactic acid bacteria isolated from healthy Chinese infant feces and traditional fermented foods such as hurood and lump milk were evaluated for the ability to tolerance acid, bile, artificial gastric juice, and artificial intestinal juice to determine the potential of the candidate strains as probiotics. Eight strains were identified as possessing superior tolerance to simulated intestinal conditions and were further analyzed by high-performance liquid chromatography (HPLC), revealing that Limosilactobacillus reuteri HCS02-001 (Lact-1) and Lacticaseibacillus paracasei HCS17-040 (Lact-2) possess the most potent ability to degrade purine nucleosides. The effect of Lact-1 and Lact-2 on hyperuricemia was evaluated by intervening with them in the potassium oxonate and adenine-induced hyperuricemia Balb/c mice model in vivo. Our results showed that the level of serum UA in hyperuricemic mice can be efficiently reduced via the oral administration of Lact-1 (p < 0.05). It significantly inhibited the levels of liver inflammatory cytokines and hepatic xanthine oxidase through a TLR4/MyD88/NF-κB pathway across the gut-liver axis. Furthermore, UA transporters ABCG2 and SLC2A9 were substantially upregulated by the intervention of this probiotic. Fecal ATP levels were significantly induced, while fecal xanthine dehydrogenase and allantoinase levels were increased following probiotics. RNA sequencing of HT-29 cells line treated with Lact-1 and its metabolites demonstrated significant regulation of pathways related to hyperuricemia. In summary, these findings demonstrate that Limosilactobacillus reuteri HCS02-001 possesses a capacity to ameliorate hyperuricemia by inhibiting UA biosynthesis via enhancing gastrointestinal barrier functions and promoting UA removal through the upregulation of urate transporters, thereby providing a basis for the probiotic formulation by targeting the gut microbiota.

Retinol dehydrogenase 12 (RDH12) knock out may cause hyperuricemia phenotype in mice

Hyperuricemia is a chronic metabolic disease caused by purine metabolism disorder. And several gene loci and transporter proteins that associated with uric acid transport functions have been identified. Retinol Dehydrogenase 12 (RDH12), recognized for its role in safeguarding photoreceptors, and our study investigated the potential impact of Rdh12 mutations on other organs and diseases, particularly hyperuricemia. We assessed Rdh12 mRNA expression levels in various tissues and conducted serum biochemical analyses in Rdh12−/− mice. Compared with the wild type, significant alterations in serum uric acid levels and kidney-related biochemical indicators have been revealed. Then further analysis, including quantitative RT-PCR of gene expression in the liver and kidney, highlighted variations in the expression levels of specific genes linked to hyperuricemia. And renal histology assessment exposed mild pathological lesions in the kidneys of Rdh12−/− mice.In summary, our study suggests that Rdh12 mutations impact not only retinal function but also contribute to hyperuricemia and renal disease phenotypes in mice. Our finding implies that individuals with Rdh12 mutations may be prone to hyperuricemia and gout, emphasizing the significance of preventive measures and regular examinations in daily life.

A Possible Therapeutic Application of the Selective Inhibitor of Urate Transporter 1, Dotinurad, for Metabolic Syndrome, Chronic Kidney Disease, and Cardiovascular Disease.

The reabsorption of uric acid (UA) is mainly mediated by urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) in the kidneys. Dotinurad inhibits URAT1 but does not inhibit other UA transporters, such as GLUT9, ATP-binding cassette transporter G2 (ABCG2), and organic anion transporter 1/3 (OAT1/3). We found that dotinurad ameliorated the metabolic parameters and renal function in hyperuricemic patients. We consider the significance of the highly selective inhibition of URAT1 by dotinurad for metabolic syndrome, chronic kidney disease (CKD), and cardiovascular disease (CVD). The selective inhibition of URAT1 by dotinurad increases urinary UA in the proximal tubules, and this un-reabsorbed UA may compete with urinary glucose for GLUT9, reducing glucose reabsorption. The inhibition by dotinurad of UA entry via URAT1 into the liver and adipose tissues increased energy expenditure and decreased lipid synthesis and inflammation in rats. Such effects may improve metabolic parameters. CKD patients accumulate uremic toxins, including indoxyl sulfate (IS), in the body. ABCG2 regulates the renal and intestinal excretion of IS, which strongly affects CKD. OAT1/3 inhibitors suppress IS uptake into the kidneys, thereby increasing plasma IS, which produces oxidative stress and induces vascular endothelial dysfunction in CKD patients. The highly selective inhibition of URAT1 by dotinurad may be beneficial for metabolic syndrome, CKD, and CVD.

Xanthoceras sorbifolium leaves alleviate hyperuricemic nephropathy by inhibiting the PI3K/AKT signaling pathway to regulate uric acid transport

Ethnopharmacological relevanceIn China, Xanthoceras sorbifolium Bunge was first documented as “Wen Guan Hua” in the “Jiu Huang Ben Cao” in 1406 A.D. According to the “National Compilation of Chinese Herbal Medicine,” X. sorbifolium leaves are sweet and flat in nature and can dispel wind and dampness, suggesting that their extract can be used to treat rheumatoid arthritis. X. sorbifolium Bunge has also been used to treat arteriosclerosis, hyperlipidemia, hypertension, chronic hepatitis, and rheumatism, complications associated with hyperuricemic nephropathy (HN), a condition characterized by kidney damage resulting from high levels of uric acid (UA) in the blood. Aim of the studyThe purpose of this study was to investigate the effects and underlying mechanisms of a 70% ethanol extract from X. sorbifolium leaves (EX) in alleviating HN. Materials and methodsA mouse model of hyperuricemia was established to initially evaluate the hypouricemic effects and determine the effective dose of EX. Phytochemical analyses were conducted using ultra high-performance liquid chromatography and liquid chromatography-mass spectroscopy. The potential key pathways of EX in the alleviation of HN were inferred using network pharmacology and bioinformatics. An HN rat model was then established, and experiments including biomarker detection, western blotting, reverse transcription quantitative polymerase chain reaction, immunohistochemical and Masson's trichrome staining, and transmission electron microscopy were conducted to evaluate the effect of EX on UA transporter expression in vitro. ResultsNetwork pharmacology and bioinformatics analyses revealed that the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway was the key pathway for the alleviation of HN progression by EX. EX treatment reduced serum biomarkers in HN rats, downregulated the expression of p-PI3K, p-AKT, glucose transporter 9 (GLUT9), urate transporter 1 (URAT1), Collagen I, matrix metalloproteinase (MMP)-2, and MMP-9, and upregulated the expression of ATP binding cassette subfamily G member 2 (ABCG2) to improve renal interstitial fibrosis in HN rats. A high content of both quercitrin and cynaroside were identified in EX; their administration inhibited the increased expression of GLUT9 and URAT1 in damaged HK-2 cells. ConclusionOur study provides evidence that EX alleviates HN. The potential mechanism underlying this effect may be the regulation of UA transporters, such as GLUT9 and URAT1, by limiting the activation of the PI3K/AKT signaling pathway to improve renal injury.

Whey Protein Peptide Pro-Glu-Trp Ameliorates Hyperuricemia by Enhancing Intestinal Uric Acid Excretion, Modulating the Gut Microbiota, and Protecting the Intestinal Barrier in Rats.

Hyperuricemia (HUA) is a metabolic disorder characterized by an increase in the concentrations of uric acid (UA) in the bloodstream, intricately linked to the onset and progression of numerous chronic diseases. The tripeptide Pro-Glu-Trp (PEW) was identified as a xanthine oxidase (XOD) inhibitory peptide derived from whey protein, which was previously shown to mitigate HUA by suppressing UA synthesis and enhancing renal UA excretion. However, the effects of PEW on the intestinal UA excretion pathway remain unclear. This study investigated the impact of PEW on alleviating HUA in rats from the perspective of intestinal UA transport, gut microbiota, and intestinal barrier. The results indicated that PEW inhibited the XOD activity in the serum, jejunum, and ileum, ameliorated intestinal morphology changes and oxidative stress, and upregulated the expression of ABCG2 and GLUT9 in the small intestine. PEW reversed gut microbiota dysbiosis by decreasing the abundance of harmful bacteria (e.g., Bacteroides, Alloprevotella, and Desulfovibrio) and increasing the abundance of beneficial microbes (e.g., Muribaculaceae, Lactobacillus, and Ruminococcus) and elevated the concentration of short-chain fatty acids. PEW upregulated the expression of occludin and ZO-1 and decreased serum IL-1β, IL-6, and TNF-α levels. Our findings suggested that PEW supplementation ameliorated HUA by enhancing intestinal UA excretion, modulating the gut microbiota, and restoring the intestinal barrier function.

Chinese Sumac (Rhus chinensis Mill.) Fruits Prevent Hyperuricemia and Uric Acid Nephropathy in Mice Fed a High-Purine Yeast Diet.

Hyperuricemia (HUA) is a prevalent chronic disease, characterized by excessive blood uric acid levels, that poses a significant health risk. In this study, the preventive effects and potential mechanisms of ethanol extracts from Chinese sumac (Rhus chinensis Mill.) fruits on HUA and uric acid nephropathy were comprehensively investigated. The results demonstrated a significant reduction in uric acid levels in hyperuricemia mice after treatment with Chinese sumac fruit extract, especially in the high-dose group, where the blood uric acid level decreased by 39.56%. Visual diagrams of the kidneys and hematoxylin and eosin (H&E)-stained sections showed the extract's effectiveness in protecting against kidney damage caused by excessive uric acid. Further investigation into its mechanism revealed that the extract prevents and treats hyperuricemia by decreasing uric acid production, enhancing uric acid excretion, and mitigating the oxidative stress and inflammatory reactions induced by excessive uric acid in the kidneys. Specifically, the extract markedly decreased xanthine oxidase (XOD) levels and expression in the liver, elevated the expression of uric acid transporters ABCG2, and lowered the expression of uric acid reabsorption proteins URAT1 and SLC2A9. Simultaneously, it significantly elevated the levels of endogenous antioxidant enzymes (SOD and GSH) while reducing the level of malondialdehyde (MDA). Furthermore, the expression of uric-acid-related proteins NLRP3, ACS, and Caspase-3 and the levels of IL-1β and IL-6 were significantly reduced. The experimental results confirm that Chinese sumac fruit extract can improve HUA and uric acid nephropathy in mice fed a high-purine yeast diet. This finding establishes a theoretical foundation for developing Chinese sumac fruit as a functional food or medicine for preventing and treating HUA.

Uric Acid Metabolism, Uric Acid Transporters and Dysuricemia

Serum urate levels are determined by the balance between uric acid production and uric acid excretion capacity from the kidneys and intestinal tract. Dysuricemia, including hyperuricemia and hypouricemia, develops when the balance shifts towards an increase or a decrease in the uric acid pool. Hyperuricemia is mostly a multifactorial genetic disorder involving several disease susceptibility genes and environmental factors. Hypouricemia, on the other hand, is caused by genetic abnormalities. The main genes involved in dysuricemia are xanthine oxidoreductase, an enzyme that produces uric acid, and the urate transporters urate transporter 1/solute carrier family 22 member 12 (URAT1/SLC22A12), glucose transporter 9/solute carrier family 2 member 9 (GLUT9/SLC2A9) and ATP binding cassette subfamily G member 2 (ABCG2). Deficiency of xanthine oxidoreductase results in xanthinuria, a rare disease with marked hypouricemia. Xanthinuria can be due to a single deficiency of xanthine oxidoreductase or in combination with aldehyde oxidase deficiency as well. The latter is caused by a deficiency in molybdenum cofactor sulfurase, which is responsible for adding sulphur atoms to the molybdenum cofactor required for xanthine oxidoreductase and aldehyde oxidase to exert their action. URAT1/SLC22A12 and GLUT9/SLC2A9 are involved in urate reabsorption and their deficiency leads to renal hypouricemia, a condition that is common in Japanese due to URAT1/SLC22A12 deficiency. On the other hand, ABCG2 is involved in the secretion of urate, and many Japanese have single nucleotide polymorphisms that result in its reduced function, leading to hyperuricemia. In particular, severe dysfunction of ABCG2 leads to hyperuricemia with reduced extrarenal excretion.

The Effects of Xanthine Oxidase Inhibitors on the Management of Cardiovascular Diseases

The Effects of Xanthine Oxidase Inhibitors on the Management of Cardiovascular Diseases

Role of Flavonoids in Combating Hyperuricemia

Individuals tend to have an increased blood uric acid level at a younger age due to their dietary choices and lifestyle, which can lead to major health concerns such as hyperuricemia, gout, cardiovascular disease, nephropathy, and inflammation. Flavonoids have been proven to have strong inhibitory action against xanthine oxidase and be able to lower serum uric acid levels, levels of adenosine deaminase, gene expressions of renal glucose transporter type 9 (mGLUT9) and uric acid transporter 1 (mURAT1), along with increased expression of organic anion transporters (mOAT1 and mOAT3) and organic cation transporters (mOCT1 and mOCT2). Furthermore, flavonoids enhanced renal function and antioxidant activity in hyperuricemic rats. In hyperuricemic mice, genistein reduced renal fibrosis by inhibiting the JAK2/STAT3 and Wnt/β-catenin signaling pathways. Overall, this review reveals that the flavonoids have substantial anti-hyperuricemia and associated disease potential and may be utilized as natural supplements for the treatment of Uric acid-related illnesses.

The anti-hyperuricemic and gut microbiota regulatory effects of a novel purine assimilatory strain, Lactiplantibacillus plantarum X7022.

Probiotics have been reported to effectively alleviate hyperuricemia and regulate the gut microbiota. The aim of this work was to study the in vivo anti-hyperuricemic properties and the mechanism of a novel strain, Lactiplantibacillus plantarum X7022. Purine content and mRNA expression of purine assimilation related enzymes were determined by HPLC and qPCR, respectively. Hyperuricemic mice were induced by potassium oxonate and hypoxanthine. Uric acid (UA), blood urea nitrogen, creatinine and renal inflammation were examined by kits. The expression of renal UA transporters was subjected to western blotting. Kidney tissues were sectioned for histological analysis. The fecal short-chain fatty acids (SCFAs) were determined by HPLC, and gut microbiota was investigated using the 16S rDNA metagenomic sequencing. L. plantarum X7022 possesses a complete purine assimilation pathway and can exhaust xanthine, guanine, and adenine by 82.1%, 33.1%, and 12.6%, respectively. The strain exhibited gastrointestinal viability as 44% at the dose of 109CFU/mL in mice. After four-week administration of the strain, a significant decrease of 35.5% in the serum UA level in hyperuricemic mice was achieved. The diminished contents of fecal propionate and butyrate were dramatically boosted. The treatment also alleviated renal inflammation and restored renal damage. The above physiological changes may due to the inhibited xanthine oxidase (XO) activity, as well as the expressional regulation of UA transporters (GLUT9, URAT1 and OAT1) to the normal level. Notably, gut microbiota dysbiosis in hyperuricemic mice was improved with the inflammation and hyperuricemia related flora depressed, and SCFAs production related flora promoted. The strain is a promising probiotic strain for ameliorating hyperuricemia.

Understanding Hyperuricemia: Pathogenesis, Potential Therapeutic Role of Bioactive Peptides, and Assessing Bioactive Peptide Advantages and Challenges.

Hyperuricemia is a medical condition characterized by an elevated level of serum uric acid, closely associated with other metabolic disorders, and its global incidence rate is increasing. Increased synthesis or decreased excretion of uric acid can lead to hyperuricemia. Protein peptides from various food sources have demonstrated potential in treating hyperuricemia, including marine organisms, ovalbumin, milk, nuts, rice, legumes, mushrooms, and protein-rich processing by-products. Through in vitro experiments and the establishment of cell or animal models, it has been proven that these peptides exhibit anti-hyperuricemia biological activities by inhibiting xanthine oxidase activity, downregulating key enzymes in purine metabolism, regulating the expression level of uric acid transporters, and restoring the composition of the intestinal flora. Protein peptides derived from food offer advantages such as a wide range of sources, significant therapeutic benefits, and minimal adverse effects. However, they also face challenges in terms of commercialization. The findings of this review contribute to a better understanding of hyperuricemia and peptides with hyperuricemia-alleviating activity. Furthermore, they provide a theoretical reference for developing new functional foods suitable for individuals with hyperuricemia.

Intestine-Targeted Explosive Hydrogel Microsphere Promotes Uric Acid Excretion for Gout Therapy.

Uric acid metabolism disorder triggers metabolic diseases, especially gout. However, increasing uric acid excretion remains a challenge. Here, an accelerative uric acid excretion pathway via an oral intestine-explosive hydrogel microsphere merely containing uricase and dopamine is reported. After oral administration, uricase is exposed and immobilized on intestinal mucosa along with an in situ dopamine polymerization via a cascade reaction triggered by the intestinal specific environment. By this means, trace amount of uricase is required to in situ up-regulate uric acid transporter proteins of intestinal epithelial cells, causing accelerated intestinal uric acid excretion. From in vitro data, the uric acid in fecal samples from gout patients could be significantly reduced by up to 37% by the mimic mucosa-immobilized uricase on the isolated porcine tissues. Both hyperuricemia and acute gouty arthritis in vivo mouse models confirm the uric acid excretion efficacy of intestine-explosive hydrogel microspheres. Fecal uric acid excretion is increased around 30% and blood uric acid is reduced more than 70%. In addition, 16S ribosomal RNA sequencing showed that the microspheres optimized intestinal flora composition as well. In conclusion, a unique pathway via the intestine in situ regulation to realize an efficient uric acid intestinal excretion for gout therapy is developed.

TCM and related active compounds in the treatment of gout: the regulation of signaling pathway and urate transporter

Gout represents a metabolic ailment resulting from the accumulation of monosodium urate crystals within joints, causing both inflammation and, harm to tissues. The primary contributor to gout’s emergence is an elevated presence of serum urate, which is under the regulation of kidney and, gut urate transporters. Mitigating this risk factor is crucial for averting gout’s onset. Several treatments rooted in TCM and related active compounds have demonstrated efficacy in managing gout, skillfully regulating serum uric acid (UA) levels and curbing inflammation’s progression. This analysis compiles key foundational research concerning the molecular signaling pathways and UA transporters linked to gout, under the regulation of TCM. The focus includes individual botanical drug, active compounds, and TCM formulations, which have been consolidated and examined in this overview. The primary keywords chosen were “gout, hyperuricemia, gouty arthritis, traditional Chinese medicine, Chinese botanical drug, medicinal botanical drug, and natural plant”. Various relevant literature published within the last 5 years were gathered from electronic databases, including PubMed, Web of Science, CNKI, and others. The findings revealed that TCM has the capacity to modulate various signaling pathways, including MAPK, NF-κB, PI3K/Akt, NLRP3 and JAK/STAT. Additionally, it impacts UA transporters like URAT1, GLUT9, ABCG2, as well as OATs and OCTs, thereby contributing to gout treatment. TCM helps maintain a balanced inflammatory interaction and facilitates UA excretion. This study enhances our understanding of TCM’s anti-gout mechanisms and introduces novel perspectives for establishing the clinical significance and future prospects of TCM-based gout treatment.

Anti-hyperuricemic properties and mechanism of Lactiplantibacillus plantarum X7023

The study conducted on Lactiplantibacillus plantarum X7023, a novel strain isolated from stinky tofu brine, aimed to investigate its effects on hyperuricemia. The strain demonstrated high in vitro gastrointestinal survivability and purine-lowering ability (guanine, xanthine and adenine decreased by 21.4%, 93.9% and 11.5%, respectively). The anti-hyperuricemia effects of the strain have been studied in potassium oxonate and hypoxanthine induced hyperuricemia mice. The serum uric acid (UA) levels of hyperuricemic mice were significantly reduced by 38.8% and 19.0% after treatment with low and high dose of L. plantarum X7023 treatment, respectively. Additionally, the levels of creatinine and blood urea nitrogen were decreased by 19.6% and 21.2% respectively in low dose of L. plantarum X7023 group. The anti-hyperuricemic mechanism of L. plantarum X7023 might be its inhibiting xanthine oxidase (XOD) activity, and regulating the expression of renal UA transporters. According to kidney inflammatory cytokines and histopathological analysis, L. plantarum X7023 could also alleviate the kidney inflammation and protect the kidney. Therefore, L. plantarum X7023 is a potential probiotic strain for the amelioration of hyperuricemia. This study further demonstrated that there are significant correlations among UA level, oxidative stress, kidney inflammation, XOD activity and UA transporter expressions in hyperuricemic mice.

A novel strain of Levilactobacillus brevis PDD-5 isolated from salty vegetables has beneficial effects on hyperuricemia through anti-inflammation and improvement of kidney damage

Hyperuricemia is a metabolic disorder caused by abnormal purine metabolism, resulting in abnormally high serum uric acid. In this study, a novel Levilactobacillus brevis PDD-5 isolated from salty vegetables was verified with the function of alleviating hyperuricemia. The relevant effects of L. brevis PDD-5 in lowering uric acid were analyzed by in vitro and in vivo experiments. The results showed that the L. brevis PDD-5 has (68.86 ± 15.46)% of inosine uptake capacity and (95.75 ± 3.30)% of guanosine uptake capacity in vitro. Oral administration of L. brevis PDD-5 to hyperuricemia rats reduced uric acid, creatinine, and urea nitrogen in serum, as well as decreased inosine and guanosine levels in the intestinal contents of rats. Analysis of relevant markers in the kidney by ELISA kits revealed that L. brevis PDD-5 alleviated oxidative stress and inflammation. Moreover, the gene expression of uric acid transporter 1 (URAT1) and glucose transporter 9 (GLUT9) was down-regulated, and the gene expression of organic anion transporter 1 (OAT1) was up-regulated after treatment with L. brevis PDD-5. Western blot analysis showed that L. brevis PDD-5 alleviated hyperuricemia-induced kidney injury through the NLRP3 pathway. These findings suggest that L. brevis PDD-5 can lower uric acid, repair kidney damage, and also has the potential to prevent uric acid nephropathy.

Molecular mechanisms regulating uric acid metabolism in the human intestine, systematic literature review

This review presents recent data on direct and indirect pathogenetic relationships between metabolism of purine compounds and biochemical processes in cells of the digestive system. A comprehensive analysis of available modern publications for the period from 2000 to 2022 in the Scopus, PubMed, eLIIBRARY, and Google Scholar databases was performed. The hypothesis linking the pathogenesis of hyperuricemia to “renal overload” suggests that the disease may develop due to impaired renal excretion with insufficient excretion of uric acid (UA) via the intestine. Some of the UA transport systems work actively in hepatocytes and enterocytes, which determines their formation and excretion. UA transporter proteins are divided into two categories: urate reabsorption transporters and urate excretion transporters; their expression is regulated by transcription factors, hormones, and metabolites of the intestinal microflora. The influence of intestinal microbiota on UA metabolism is associated with its involvement in purine metabolism, degradation and excretion of UA together with metabolites of intestinal flora, and suppression of gout inflammation, and is evaluated as a new therapeutic potential for gout and hyperuricemia to prevent renal damage and urolithiasis.

Cinnamon essential oil based on NLRP3 inflammasome and renal uric acid transporters for hyperuricemia

Cinnamon is widely used as a medicinal herb and a culinary spice. The major bioactive component of cinnamon is cinnamon essential oil (CEO). CEO has been reported to have anti-inflammatory and antioxidant effects, but its mechanism of action is not known. In this study, metabolomics was combined with “weighting coefficients” from network pharmacology to identify key pathways and targets, differential metabolites and key metabolic pathways for the therapeutic effects of CEO on Hyperuricemia (HUA), and to precisely investigate the molecular mechanisms of the therapeutic effects of CEO on HUA. Metabolomic analysis revealed that abnormal l-glutamate metabolism and dysregulation of Arachidonic acid (AA) metabolic pathways exacerbated inflammatory responses and oxidative stress, subsequently mediating pathological changes in HUA and exacerbating renal tissue damage. Pharmacodynamic validation showed that CEO alleviated the renal inflammatory response by inhibiting hepatic xanthine oxidase activity, upregulating superoxide dismutase and glutathione peroxidase levels, and downregulating malondialdehyde levels, synergistically inhibiting NLRP3 inflammasome activation, suppressing downstream inflammatory Interleukin-1 beta (IL-1β) and Interleukin-18 (IL-18) secretion, and enhancing antioxidant levels. Additionally, CEO exerted renal protective effects by upregulating the renal transporters OAT1 and ABCG2 and downregulating the GLUT9 and URAT1 levels, resulting in the downregulation of uric acid production and the alleviation of renal tubular lesions. This suggests that CEO could be considered as a potential functional food for kidney damage caused by hyperuricemia.

Systematic review and model-based analysis to identify whether renal safety risks of URAT1 inhibitors are fully determined by uric acid-lowering efficacies

ObjectiveRenal safety risk is currently an important factor that hinders the development of uric acid transporter 1 (URAT1) inhibitors. This study aimed to compare the renal safety and uric acid-lowering efficacy of different URAT1 inhibitors and clarify the association between them. MethodsA systematic review of published randomized controlled trials on URAT1 inhibitors was conducted to investigate the incidence of renal safety events. A model-based analysis was performed to predict the uric acid-lowering efficacy of representative URAT1 inhibitors. ResultsThe overall renal safety event incidences of lesinurad, verinurad, dotinurad, SHR4640, and benzbromarone in patients with hyperuricemia were 11.2 % (142/1264), 12.0 % (34/284), 0.5 % (2/421), 2.3 % (5/213), and 1.3 % (5/393), respectively. A semi-mechanistic pharmacokinetic/pharmacodynamic model was used to establish the dose–exposure–effect relationship of lesinurad, verinurad, dotinurad, and SHR4640 with or without the combination of xanthine oxidase inhibitors (XOIs). The efficacy ranking of the intermediate dose of URAT1 inhibitors with once-daily dosing was 2 mg dotinurad > 10 mg verinurad > 5 mg SHR4640 > 400 mg lesinurad. The combination of 80 mg febuxostat and 600 mg allopurinol reduced the 24-h cumulative renal uric acid excretion by 48.4 % and 48.3 %, respectively. ConclusionUric acid-lowering efficacy is not an independent factor for the renal safety risk of different URAT1 inhibitors, and structural differences could be responsible for the difference. The adverse renal effects of URAT1 inhibitors are dose-dependent, and the combination with high doses of XOIs can significantly reduce the renal safety risk by reducing uric acid excretion by the kidneys.

Mammary gland, kidney and rumen urea and uric acid transporters of dairy cows differing in milk urea concentration

The milk urea concentration (MUC) serves as indicator of urinary nitrogen emissions, but at comparable crude protein (CP) intake, cows with high (HMU) and low (LMU) MUC excrete equal urea amounts. We hypothesized that urea and uric acid transporters and sizes of the kidney, mammary gland, and rumen account for these phenotypes. Eighteen HMU and 18 LMU Holstein dairy cows fed a low (LP) and normal (NP) CP diet were studied. Milk, plasma and urinary urea concentrations were greater with NP feeding, while plasma and urinary urea concentrations were comparable between phenotypes. Milk and plasma uric acid concentrations were higher with LP feeding but not affected by phenotype. The milk-urine uric acid ratio was greater in HMU cows. The mRNA expressions of the ruminal urea transporter SLC14A1 and AQP10, the mammary gland and rumen AQP3, and the mammary gland uric acid transporter ABCG2 were not affected by group or diet. Renal AQP10, but not AQP3, AQP7, and SLC14A2 expressions, and the kidney weights were lower in HMU cows. These data indicate that renal size and AQP10 limit the urea transfer from blood to urine, and that MUC determines if uric acid is more released with milk or urine.