2023 Volume 47 Issue 2 Pages 99-106
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.
