Urate Transporter URAT1 in Hyperuricemia: New Insights from Hyperuricemic Models

Hyperuricemia (HUA) is positively correlated with the progression of cardiovascular and metabolic diseases. Anti-HUA drugs aim to either reduce uric acid production or promote uric acid excretion. Urate transporter 1 (URAT1) is a major urate transporter involved in renal uric acid reabsorption and excretion, making it an important anti-HUA drug target. To better understand the characteristics of URAT1 under pathological conditions, the present study aims to investigate URAT1 modulation in HUA mouse and cell line models. We found that URAT1 expression increased in the kidneys of HUA mice with normal renal function, but decreased in HUA mice with kidney injury (KI-HUA). In KI-HUA mice, treatment with anti-HUA agents, febuxostat, and benzbromarone decreased uric acid levels. However, febuxostat treatment also decreased URAT1 expression, whereas benzbromarone treatment increased its expression. Based on these in vivo findings, we propose that extracellular uric acid levels in the proximal tubule epithelial cells positively regulated URAT1 expression. In high uric acid cell models, URAT1 expression increased within 2 h of uric acid stimulation in a dose-dependent manner that supported our hypothesis. Therefore, our results suggest that URAT1 expression is positively regulated by the distinct extracellular uric acid levels in different HUA models.