URAT1

BACKGROUND: Patients with deficient hypoxanthine-guanine phosphoribosyltransferase (HPRT) activity present hyperuricemia and/or hyperuricosuria, with a variable degree of neurological manifestations. Hyperuricemia in HPRT deficiency is due to uric acid overproduction and is frequently treated with allopurinol. Renal uric acid excretion is sharply increased in these patients. In recent years, several renal tubular urate transporter single nucleotide polymorphisms (SNPs), including those of the GLUT9, ABCG2 and URAT1 genes, have been described that influence the renal handling of uric acid and modulate serum urate levels...

Objectives: Verinurad (RDEA3170) is a high-affinity inhibitor of the URAT1 transporter in clinical development for treating gout and asymptomatic hyperuricaemia. The aim of this Phase 2a, randomized, open-label study was to investigate the multiple-dose pharmacodynamics, pharmacokinetics and safety of oral verinurad combined with febuxostat vs febuxostat alone and verinurad alone. Methods: Japanese male subjects aged 21-65 years with gout (n = 37) or asymptomatic hyperuricaemia (n = 35) and serum urate (sUA) ⩾8 mg/dl were randomized to febuxostat (10, 20, 40 mg) in combination with verinurad (2...

PURPOSE OF REVIEW: Uric acid homeostasis in the body is mediated by a number of SLC and ABC transporters in the kidney and intestine, including several multispecific 'drug' transporters (e.g., OAT1, OAT3, and ABCG2). Optimization of uric acid levels can be viewed as a 'systems biology' problem. Here, we consider uric acid transporters from a systems physiology perspective using the framework of the 'Remote Sensing and Signaling Hypothesis.' This hypothesis explains how SLC and ABC 'drug' and other transporters mediate interorgan and interorganismal communication (e...

BACKGROUND/AIMS: Zurampic is a US FDA approved drug for treatment of gout. However, the influence of Zurampic on pancreatic β-cells remains unclear. The study aimed to evaluate the effects of Zurampic on high uric acid-induced damage of pancreatic β-cells and the possible underlying mechanisms. METHODS: INS-1 cells and primary rat islets were stimulated with Zurampic and the mRNA expression of urate transporter 1 (URAT1) was assessed by qRT-PCR. Cells were stimulated with uric acid or uric acid plus Zurampic, and cell viability, apoptosis and ROS release were measured by MTT and flow cytometry assays...

Searching novel hypouricemic agents of high efficacy and safety has attracted a great attention. Previously, we reported the hypouricemic effect of Ganoderma applanatum , but its bioactives, was not referred. Herein, we report the hypouricemic effect of 2,5-dihydroxyacetophenone (DHAP), a compound screened from Ganoderma applanatum computationally. Serum parameters, such as uric acid (SUA), xanthine oxidase (XOD) activity, blood urea nitrogen (BUN), and creatinine were recorded. Real-time reverse transcription PCR (RT-PCR) and Western blot were exploited to assay RNA and protein expressions of organic anion transporter 1 (OAT1), glucose transporter 9 (GLUT9), uric acid transporter 1 (URAT1), and gastrointestinal concentrative nucleoside transporter 2 (CNT2)...

BACKGROUND: Multiple risk factors contribute to the progression of Parkinson's disease, including oxidative stress and neuroinflammation. Epidemiological studies have revealed a link between higher urate level and a lower risk of developing PD. However, the mechanistic basis for this association remains unclear. Urate protects dopaminergic neurons from cell death induced by oxidative stress. Here, we investigated a novel role of urate in microglia activation in a lipopolysaccharide (LPS)-induced PD model...

A mangiferin aglycon derivative J99745 has been identified as a potent xanthine oxidase (XOD) inhibitor by previous in vitro study. This study aimed to evaluate the hypouricemic effects of J99745 in experimental hyperuricemia mice, and explore the underlying mechanisms. Mice were orally administered 600 mg/kg xanthine once daily for 7 days and intraperitoneally injected 250 mg/kg oxonic acid on the 7th day to induce hyperuricemia. Meanwhile, J99745 (3, 10, and 30 mg/kg), allopurinol (20 mg/kg) or benzbromarone (20 mg/kg) were orally administered to mice for 7 days...

Objective: Verinurad (RDEA3170) is a high-affinity, selective URAT1 inhibitor in development for treating gout and asymptomatic hyperuricaemia. This study evaluated the pharmacodynamics, pharmacokinetics and safety of verinurad in combination with febuxostat in adults with gout. Methods: The phase IIa, open-label, multicentre study randomised 64 subjects into one of five cohorts to receive febuxostat (40 or 80 mg) alone or in combination with verinurad 2.5-20 mg...

The purpose of this study was to create novel urate under-excretion animal models using pyrazinamide and to evaluate whether dihydropyridine calcium channel blockers (CCBs) have uricosuric effects in vivo. Adult male ICR mice were treated with pyrazinamide, vehicle (dimethyl sulfoxide: DMSO), or tap water. Thirty minutes later, pyrazinamide-treated mice were given benzbromarone, losartan, nilvadipine, nitrendipine, nifedipine or azelnidipine. Six hours after the second administration, urine (by urinary bladder puncture) and plasma were collected to measure uric acid and creatinine levels, and fractional excretion of uric acid (FEUA) and creatinine clearance (Ccr) were calculated and evaluated...

High levels of uric acid (UA) are associated with type-2 diabetes and cardiovascular disease. Recent pieces of evidence attributed to UA a causative role in the appearance of diabetes and vascular damage. However, the molecular mechanisms by which UA induces these alterations have not been completely elucidated so far. Among the mechanisms underlying insulin resistance, it was reported the role of a transmembrane glycoprotein, named either ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) or plasma cell antigen 1, which is able to inhibit the function of insulin receptor (IR ) and it is overexpressed in insulin-resistant subjects...

Objectives: Verinurad (RDEA3170) is a high affinity, selective uric acid transporter (URAT1) inhibitor indevelopment for treating gout and asymptomatic hyperuricaemia. This phase IIa study evaluated the pharmacodynamics, pharmacokinetics and safety of verinurad combined with allopurinol versus allopurinol alone in adults with gout. Methods: Forty-one subjects were randomised into two cohorts of verinurad (2.5-20 mg) plus allopurinol (300 mg once daily) versus allopurinol 300 mg once daily, 600 mg once daily or 300 mg twice daily alone...

BACKGROUND/AIMS: The objective of this study is to evaluate the hypouricemic and nephroprotective effects of an active fraction from Polyrhachis vicina Roger (AFPR) in potassium oxonate-induced hyperuricemic rats. METHODS: Hyperuricemia was induced by potassium oxonate in male rats. AFPR was orally administered to hyperuricemic rats for 12 consecutive weeks. Serum, liver and kidney samples were collected for effects and mechanism analysis. The levels of serum uric acid (SUA) were measured by the phosphotungstic acid method, xanthine oxidase (XOD) activity in the hepatic and serum samples were measured by ultraviolet spectrophotometry, serum levels of interleukin-1 (IL-1β), interleukin-1 (IL-6) and tumor necrosis factor-α (TNF-α) were measured by ELISA, the levels of serum creatinine (SCr), blood urea nitrogen (BUN), super oxide dismutase (SOD) and malondialdehyde (MDA) in serum were determined by colorimetric method...

BACKGROUND: Renal hypouricemia (RHUC), a rare inherited disorder characterized by impaired uric acid (UA) reabsorption in the proximal tubule, is caused by mutations in SLC22A12 or SLC2A9. Most mutations have been identified in Japanese patients, and only a few have been detected in Europeans. METHODS: We report clinical, biochemical and genetics findings of fourteen Spanish patients, six Caucasians and eight of Roma ethnia, diagnosed with idiopathic RHUC. Two of the patients presented exercise-induced acute renal failure and another one had several episodes of nephrolithiasis and four of them had progressive deterioration of renal function, while the rest were asymptomatic...

Recently, we've reported the anti-hyperuricemic effects of Cordyceps militaris . As a characteristic compound of C. militaris , we hypothesized that cordycepin may play a role in preventing hyperurecimia. Remarkably, cordycepin produced important anti-hyperuricemic actions, decreasing SUA (serum uric acid) to 216, 210, and 203 μmol/L ( P < 0.01) at 15, 30, and 60 mg/kg in comparison of hyperuricemic control (337 μmol/L), closing to normal control (202 μmol/L). Elisa, RT-PCR and western blot analysis demonstrated that the actions may be attributed to its downregulation of uric acid transporter 1 (URAT1) in kidney...

BACKGROUND: Uric acid (UA) stones are responsible for 5-10% of the formation of all kidney stones. Recently, an association between UA stones and insulin resistance, diabetes mellitus, and obesity has been demonstrated and so the incidence has increased. The development of UA stones is dependent on several risk factors, including genetic predisposition, geographical location, dietary indiscretion, and various metabolic characteristics. SUMMARY: UA nephrolithiasis can arise from diverse etiologies, all with distinct underlying defects converging to one or more of 3 defects of hyperuricosuria, acidic urine pH, and low urinary volume...

Uric acid (UA) remains a risk factor for the progression of chronic kidney disease (CKD). Most observational studies showed a slight elevation in the serum UA level and this independently predicts the incidence and development of CKD. The recent meta-analysis, however, did not reach the conclusion that urate-lowering therapy with allopurinol retards the progression of CKD. The target level of serum UA if treated is another issue of debate. Our recent analysis by propensity score analysis has shown that the serum UA should be targeted below 6...

Hyperuricemia occurs in 21.4% of the adult population and is associated with several conditions that increase oxidative stress and contributes to the pathogenesis of inflammatory mechanisms for the development and progression of diseases. Serum blood or urine samples of uric acid levels were used to mainly identify clinical problems, depending on the uric acid pathway alterations, which include synthesis, reabsorption or its excretion. Several proteins that act particularly as transporters (URAT1, GLUT9, 1-NPT1, 1-NPT4, OAT4, 9-MCT9, hUAT1, etc...

In order to systematically explore and better understand the structure-activity relationship (SAR) of a diarylmethane backbone in the design of potent uric acid transporter 1 (URAT1) inhibitors, 33 compounds ( 1a - 1x and 1ha - 1hi ) were designed and synthesized, and their in vitro URAT1 inhibitory activities (IC50 ) were determined. The three-round systematic SAR exploration led to the discovery of a highly potent novel URAT1 inhibitor, 1h , which was 200- and 8-fold more potent than parent lesinurad and benzbromarone, respectively (IC50 = 0...

The SLC22 transporter family consists of more than two dozen members, which are expressed in the kidney, the liver, and other tissues. Evolutionary analysis indicates that SLC22 transporters fall into at least six subfamilies: OAT (organic anion transporter), OAT-like, OAT-related, OCT (organic cation transporter), OCTN (organic cation/carnitine transporter), and OCT/OCTN-related. Some-including OAT1 [SLC22A6 or NKT (novel kidney transporter)] and OAT3 (SLC22A8), as well as OCT1 (SLC22A1) and OCT2 (SLC22A2)-are widely studied drug transporters...

Uric acid is the product of purine metabolism and its increased levels result in hyperuricemia. A number of epidemiological reports link hyperuricemia with multiple disorders, such as kidney diseases, cardiovascular diseases and diabetes. Recent studies also showed that expression and functional changes of urate transporters are associated with hyperuricemia. Uric acid transporters are divided into two categories: urate reabsorption transporters, including urate anion transporter 1 (URAT1), organic anion transporter 4 (OAT4) and glucose transporter 9 (GLUT9), and urate excretion transporetrs, including OAT1, OAT3, urate transporter (UAT), multidrug resistance protein 4 (MRP4/ABCC4), ABCG-2 and sodium-dependent phosphate transport protein...