It remains inconclusive whether urate-lowering therapy for asymptomatic patients with hyperuricemia is effective to prevent chronic kidney diseases (CKD) and atherosclerotic cardiovascular diseases (CVD). Hyperuricemia is caused by reduced renal/extrarenal excretion and overproduction of uric acid. It is affected by the genetic predisposition for uric acid transporters and also by visceral fat accumulation due to overnutrition. Since patients with hyperuricemia comprise a heterogeneous population based on complex pathologies, it may be important to assess whether outcomes are the result of decreasing serum uric acid levels or the inhibitory effect on xanthine oxidoreductase (XOR). This minireview focuses mainly on recent papers investigating the relationship between hyperuricemia and CKD or CVD, and intervention studies involving urate-lowering therapy. Accumulating experimental studies have proposed mechanistic insights into renal damage and atherosclerosis in hyperuricemia, including inflammasome activation, decreased nitric oxide bioavailability and oxidative stress by uric acid, urate crystals, and XOR-mediated reactive oxygen species. Recently, strong positive correlations between plasma XOR activity and liver enzymes have been shown in clinical studies. Especially in the presence of NAFLD, excessive plasma XOR derived from liver accelerates purine catabolism in the circulation, using hypoxanthine secreted from vascular endothelial cells and adipocytes, which can promote the development of vascular remodeling. Furthermore, the XOR inhibitor topiroxostat improved arterial stiffness parameters in hyperuricemic patients with liver dysfunction, which may be related to its inhibitory effect on plasma XOR. In this review, we focused on the significance of liver-derived XOR and XOR inhibition in the development of arteriosclerosis.
Hypouricemia and hyperuricemia in children are important clinical problems. Exercise‑induced acute renal injury (EIAKI) is a major complication in patients with renal hypouricemia and is more common in young patients. Hyperuricemia in children has been linked to obesity, metabolic syndrome, hypertension, glucose intolerance, dyslipidemia, and non‑alcoholic fatty liver disease (NAFLD), and is a risk factor for future development of lifestyle‑related diseases. Recently, we conducted a population‑based cross‑sectional study to measure the prevalences of hypouricemia and hyperuricemia, and identify the associated factors based on the results of pediatric health check‑ups in Kagawa prefecture. Among 31,822 9‑10‑year‑old participants, hypouricemia (serum UA ≤ 2 mg/dL) was detected in 122 [0.38%] participants (57 boys [0.35%] and 65 girls [0.41%]), which is consistent with previously reported prevalences in Japanese adults. The prevalence of hypouricemia was not significantly associated with age, sex, or environmental factors, including overweight. Furthermore, the results indicated that the differential diagnosis of renal hypouricemia is better with serum uric acid levels ≤ 2.0 mg/dL than ≤ 2.5 mg/dL in children as in adults. Hyperuricemia (serum UA ≥ 6.0 mg/dL) was detected in 734 [2.3%] participants (437 boys [2.7%] and 297 girls [1.9%]). The prevalence of hyperuricemia was significantly associated with age, sex, overweight, future diabetes risk, hypertriglyceridemia, low high‑density lipoprotein‑cholesterol, and liver damage, but not with high low‑density lipoprotein cholesterol. Further longitudinal studies are needed to determine the long‑term prognosis of children with hypouricemia and hyperuricemia and the effectiveness of interventions.
Background and Objective: Fasting decreases urinary urate (UA) excretion by half in uricase (Uox) - knockout (KO) mice, an animal model of hyperuricemia. We speculated that rodents are heavily influenced by dietary purine intake. However, there are no reports on the differences in purine content in animal diets or their effects on UA kinetics. In this study, we measured the purine content in standard and purified diets to investigate the effect of a purified diet on UA kinetics in high hypoxanthine phosphoribosyltransferase (HPRT) - activity Uox - KO mice.
Methods: The purine contents of a standard diet, Charles River Formula-1 (CRF-1), and a purified diet, AIN93M, were measured using a peak-shift assay with xanthine oxidase (XO) treatment and HPLC. Wild-type (WT) and high HPRT-activity Uox - KO mice were fed the CRF-1 or AIN93M diet for seven days to evaluate the effects of dietary purine intake on UA-related parameters.
Results: The purine content of AIN93M was approximately one-seventeenth times lower than that of CRF-1. The WT mice showed no significant variation in UA-related parameters in the AIN93M group compared with that in the CRF-1 group; however, the urinary allantoin/creatinine ratio was decreased. Conversely, the AIN93M group showed significantly decreased plasma UA levels and urinary UA/creatinine ratios than those in the CRF-1 group of high HPRT-activityUox - KO mice.
Conclusion: High HPRT-activity Uox - KO mice were useful for evaluating the variation in UA kinetics induced by dietary therapy. Additionally, a low-purine diet decreased plasma UA levels and urinary UA excretion in a mouse model of hyperuricemia.
Xanthine oxidoreductase (XOR) is an enzyme that catalyzes uric acid production by catabolizing hypoxanthine, an intermediate product of the synthesis and degradation of purine nucleotides, including adenosine 5'-triphosphate (ATP). Considering that hypoxanthine is utilized for purine nucleotide synthesis via the salvage pathway, XOR inhibition is expected to increase the hypoxanthine levels and enhance ATP production, leading to the treatment of various diseases. We investigated the effects of NP-1250-HU, a novel potent XOR inhibitor, on the intracellular ATP and purine levels. In the mouse vascular smooth muscle-derived cell line, NP-1250-HU decreased the uric acid levels and increased the hypoxanthine levels at concentrations of 0.3–3.0 µM. The addition of 2.0 µM NP-1250-HU to the medium significantly increased the intracellular ATP levels under hypoxic conditions and recovered cell viability upon respiratory chain inhibition. Compared to other XOR inhibitors, 2.0 µM NP-1250-HU and 10 µM febuxostat showed similar increases in the ATP levels under hypoxic conditions, but 50 µM allopurinol did not. These results suggest that NP-1250-HU contributes to increasing the ATP levels via the salvage pathway by increasing the intracellular hypoxanthine levels. This paper briefly describes a high-performance liquid chromatography method for analyzing purine compounds using caffeine as an internal standard.