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.

Regulation of Catechins in Uric Acid Metabolism Disorder Related Human Diseases

Uric acid is the end product of purine metabolism in humans. High uric acid levels form sodium urate crystals that trigger biological processes, which lead to the development of several diseases, including diabetes, hyperuricemia, gout, inflammatory disease, kidney disease, cardiovascular disease and hypertension. Catechins have been suggested to be beneficial for the regulation of uric acid metabolic disorders due to their powerful antioxidant and anti-inflammatory properties. To identify an effective and safe natural substance that can decrease levels of serum uric acid to improve uric acid metabolism disorders. A search was performed on PubMed, Web of Science and Google Scholar to identify comprehensive studies that presented summarized data on the use of catechins in lowering uric acid levels in diseases. This review details the role of catechins in inhibiting the activity of xanthine oxidase to decrease uric acid overproduction in the liver and in regulating expressions of uric acid transporters, URAT1, OAT1, OAT3, ABCG2 and GLUT9, to balance levels of uric acid secretion and reabsorption through the kidney and intestine. Additionally, Catechins were also found to prevent monosodium urate-induced inflammatory reactions. In vivo, catechins can be used to decrease high uric acid levels that result from hyperuricemia and related diseases. Catechins can be used to maintain the balance of uric acid metabolism.

Investigation of the Effects and Mechanisms of Dendrobium loddigesii Rolfe Extract on the Treatment of Gout

Objective. Gout is a chronic disease that causes inflammatory arthritis, which is closely related to urate accumulation induced by a disorder of uric acid metabolism and the consequent deposition of monosodium urate crystals. Dendrobium loddigesii Rolfe is an herbal medicine that has been used in some traditional Chinese medicine formulae in the treatment of gout. This study aimed to explore and verify the antigout activity of Dendrobium loddigesii extract (DLE) on alleviating the hyperuricaemia of mice and the acute gouty arthritis of rats. Methods. An animal model of hyperuricaemia was established using potassium oxonate (PO). We analysed the expression of uric acid transporter mRNA in the kidney in the hyperuricaemic mice after treatment with DLE. Simultaneously, a monosodium urate crystal-induced acute gouty arthritis rat model was used to evaluate the effects of DLE, according to the level of ankle swelling, as well as the protein levels of inflammatory receptors and cytokines, as assayed by WB and ELISA. Results. DLE alleviated hyperuricaemia in mice and inhibited acute gouty arthritis in rats (P<0.05). Meanwhile, DLE regulated the levels of uric acid transporters mRNA transcripts, including mouse organic anion transporter 1 (mOAT1), organic anion transporter 3 (mOAT3), urate transporter 1 (mURAT1), and glucose transporter 9 (mGLUT9) in the kidney (P<0.05), suggesting that DLE promoted uric acid metabolism. Furthermore, DLE significantly suppressed the protein levels of TLRs, MyD88, and NF-κB in the ankle joint’s synovium (P<0.05), and the serum levels of IL-1β, IL-6, and TNF-α were also reduced, which demonstrated the anti-inflammatory effects of DLE. Conclusion. DLE alleviates hyperuricaemia by regulating the transcription level of uric acid transporters in the kidney. It also inhibits acute gouty arthritis by inhibiting the pathway of TLRs/MyD88/NF-κB in the ankle joint’s synovium. The findings of the present study imply that DLE alleviates gout by promoting uric acid metabolism and inhibiting inflammation related to the TLRs/MyD88/NF-κB pathway.

P0964EFFECTS OF XANTHINE OXIDASE INHIBITORS AND DAPAGLIFLOZIN ON RENAL GLUCOSE AND URATE TRANSPORTERS IN METABOLIC SYNDROME

Background and Aims Metabolic syndrome consists of several medical conditions that collectively predict the risk for cardiovascular disease. Hyperglycemia and hyperuricemia are the major disorders of metabolic syndrome. Kidney reabsorbs almost all filtrated glucose by active transport at normal concentrations of plasma glucose via members of the sodium glucose transport (SGLT) family. Besides, the kidney plays a pivotal role in handling uric acid homeostasis. Uric acid is mainly controlled by urate transporter (UAT), urate anion exchanger 1 (URAT1) and glucose transporter 9 (GLUT9). The aims of the study were to determine the alteration of renal glucose and uric acid transporters in animals with metabolic syndrome after treatment of xanthine oxidase inhibitors and SGLT2 inhibitor. Method Sprague-Dawley rats were fed with normal chow (Control) or high fructose diet (60%) for totally 6 months. For those animals fed with high fructose diet for 3 months, they were divided into 4 groups including high fructose diet without treatment (FR), treatment with allopurinol (150 mg/L in drinking water), with febuxostat (30 mg/L in drinking water) or with dapagliflozin (1mg/kg/day intraperitoneal injection). Blood, urine and blood pressure were collected and measured at the end of study. Gene and protein expression of renal glucose and uric acid transporters were determined by reverse transcriptase polymerase chain reaction. The changes of transporters were then confirmed by immunohistochemical staining. Results High-fructose diet induced higher levels of fasting glucose, insulin resistance index, uric acid, triglyceride and blood pressure in FR group (all p &lt;0.05 vs. control). Treatment of allopurinol, febuxostat and dapagliflozin reduced body weight significantly. Fasting glucose, insulin resistance index and hyperuricemia were improved in all drug treatment groups (all p &lt;0.05). In the kidney, high fructose diet significantly upregulated SGLT1, SGLT2 and GLUT2 but downregulated GLUT1 expression. Urate transporters, including GLUT9, UAT and URAT1 were also increased (p &lt;0.05). The improvement of insulin resistance by xanthine oxidase inhibitors was associated with suppression of renal SGLT1, SGLT2 and GLUT2 expression. Dapagliflozin alleviated hyperuricemia and induced uricosuria without affecting serum xanthine oxidase activity. Compared to FR, dapagliflozin significantly inhibited fructose-induced overexpression of GLUT9, UAT and URAT1 in the kidney. Conclusion Long term high fructose diet induced metabolic syndrome in rats. Treatment of xanthine oxidase inhibitors and dapagliflozin ameliorated components of metabolic syndrome. Both allopurinol and febuxostat improved insulin resistance in association with suppression of renal SGLT1, SGLT2 and GLUT2 expression. Although dapagliflozin and xanthine oxidase inhibitors reduced uric acid in different mechanisms, they shared a similar molecular changes in the kidney by downregulating GLUT9, UAT and URAT1 expression.

Disorders of purine and pyrimidine metabolism

Disorders of purine and pyrimidine metabolism are due to abnormalities in the biosynthesis, interconversion, and degradation of the purines—adenine and guanine—and of the pyrimidines—cytosine, thymine, and uracil. The purine nucleotides, their cyclic derivatives (cAMP and cGMP), and their more highly phosphorylated derivatives have functions in many aspects of intermediary metabolism. Purine compounds also function as signal transducers, neurotransmitters, vasodilators, and mediators of platelet aggregation. Disorders of purine metabolism—the end point of purine metabolism in humans is uric acid. When uric acid levels become supersaturated in body fluids, uric acid and sodium urate monohydrate crystallize, causing gout. This results from either overproduction or underexcretion of urate, or from a combination of these defects. Decreased net tubular urate secretion is most often due to genetic polymorphism in uric acid transporters and is the commonest cause of primary (‘idiopathic’) gout. Gout may be secondary to a wide variety of renal disorders. Gout is also a consequence of enzymatic defects that accelerate de novo purine synthesis. Acute attacks of gout are treated with nonsteroidal anti-inflammatory drugs, colchicine, or steroids. Hypouricaemia may be caused by inherited disorders of uric acid biosynthesis or may be due to inherited or acquired renal tubule transport defects. Disorders of pyrimidine metabolism—the de novo synthesis of pyrimidine nucleotides involves a series of six reactions beginning with the formation of carbamyl phosphate and concluding with orotidine monophosphate, which then undergoes a series of interconversion and salvage reactions. The inherited disorders of pyrimidine metabolism, which can present in a wide variety of ways, are much less common and/or much less easily recognized than disorders of purine metabolism.

Human URAT1/SLC22A12 gene promoter is regulated by 27-hydroxycholesterol through estrogen response elements

Elevated levels of uric acid, a metabolite of purine in humans, is related to various diseases, such as gout, atherosclerosis and renal dysfunction. The excretion and reabsorption of uric acid to/from urine is tightly regulated by uric acid transporters. The amino acid sequences of uric acid reabsorption transporters, URAT1/SLC22A12, OAT4/SLC22A11, and OAT10/SLC22A13, share closer phylogenic relationship, whereas the gene promoter sequences are distant phylogenic relationship. Through the single-cell RNA-sequencing analysis of an adult human kidney, we found that only a small number of cells express these transporters, despite their role in the regulation of serum uric acid levels. Transcriptional motif analysis on these transporter genes, revealed that the URAT1/SLC22A12 gene promoter displayed the most conserved estrogen response elements (EREs) among the three transporters. The endogenous selective estrogen receptor modulator (SERM) 27-hydroxycholesterol (27HC) had positive effects on the transcriptional activity of URAT1/SLC22A12. We also found that 27HC increased the protein and gene expression of URAT1/SLC22A12 in mouse kidneys and human kidney organoids, respectively. These results strongly suggest the role of 27HC for URAT1/SLC22A12 expression in renal proximal tubules and upregulation of serum uric acid levels and also show the relationship between cholesterol metabolism and serum uric acid regulation.Significance StatementThe elevated levels of serum uric acid cause various diseases, and the excretion/reabsorption of uric acid to/from urine is tightly regulated by the uric acid transporters. We found that despite the role in serum uric acid regulation, only a small number of cells express URAT1/SLC22A12. We also found that URAT1/SLC22A12 gene promoter region has effective estrogen response elements, and endogenous selective estrogen receptor (ER) modulator 27-hydroxycholesterol (27HC) increased URAT1/SLC22A12 expression in the mice kidneys and human kidney organoids. These suggest that 27HC increases URAT1/SLC22A12 expression and upregulate serum uric acid levels. Since 27HC connects cholesterol metabolism, our study indicates the important link between cholesterol metabolism and serum uric acid regulation, and also provides a novel therapeutic approach to hyperuricemia.

Identification of a Novel Nucleobase-Ascorbate Transporter Family Member in Fish and Amphibians

Nucleobase-Ascorbate Transporter (NAT) family includes ascorbic acid, nucleobases, and uric acid transporters: With broad evolutionary distribution. In vertebrates, four members have been previously recognized, the ascorbate transporters Slc23a1 and Slc3a2, the nucleobase transporter Slc23a4 and an orphan transporter Slc23a3. Using phylogenetic and synteny analysis, we identify a fifth member of the vertebrate slc23 complement (slc23a5), present in neopterygians (gars and teleosts) and amphibians, and clarify the evolutionary relationships between the novel gene and known slc23 genes. Further comparative analysis puts forward uric acid as the preferred substrate for Slc23a5. Gene expression quantification, using available transcriptomic data, suggests kidney and testis as major expression sites in Xenopus tropicalis (western clawed frog) and Danio rerio (zebrafish). Additional expression in brain was detected in D. rerio, while in the Neoteleostei Oryzias latipes (medaka) slc23a5 expression is restricted to the brain. The biological relevance of the retention of an extra transporter in fish and amphibians is discussed.