Department of Pharmacology and Department of the Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
Peking University International Cancer Institute, Peking University Health Science Center, Beijing 100191, China.
Int J Mol Sci. 2020 Oct 18;21(20):7695. doi: 10.3390/ijms21207695.
Hyperuricemia (HUA) is a risk factor for chronic kidney disease (CKD). Serum uric acid (SUA) levels in CKD stage 3-4 patients closely correlate with hyperuricemic nephropathy (HN) morbidity. New uric acid (UA)-lowering strategies are required to prevent CKD. The multiple-purpose connectivity map (CMAP) was used to discover potential molecules against HUA and renal fibrosis. We used HUA and unilateral ureteral occlusion (UUO) model mice to verify renoprotective effects of molecules and explore related mechanisms. In vitro experiments were performed in HepG2 and NRK-52E cells induced by UA. Esculetin was the top scoring compound and lowered serum uric acid (SUA) levels with dual functions on UA excretion. Esculetin exerted these effects by inhibiting expression and activity of xanthine oxidase (XO) in liver, and modulating UA transporters in kidney. The mechanism by which esculetin suppressed XO was related to inhibiting the nuclear translocation of hexokinase 2 (HK2). Esculetin was anti-fibrotic in HUA and UUO mice through inhibiting TGF-β1-activated profibrotic signals. The renoprotection effects of esculetin in HUA mice were associated with lower SUA, alleviation of oxidative stress, and inhibition of fibrosis. Esculetin is a candidate urate-lowering drug with renoprotective activity and the ability to inhibit XO, promote excretion of UA, protect oxidative stress injury, and reduce renal fibrosis.
高尿酸血症（HUA）是慢性肾脏病（CKD）的一个风险因素。CKD 3-4 期患者的血清尿酸（SUA）水平与高尿酸血症肾病（HN）的发病率密切相关。需要新的降尿酸（UA）策略来预防 CKD。多功能连接图（CMAP）被用于发现潜在的抗 HUA 和肾纤维化的分子。我们使用 HUA 和单侧输尿管结扎（UUO）模型小鼠来验证分子的肾脏保护作用，并探索相关机制。在 HepG2 和 NRK-52E 细胞中进行了 UA 诱导的体外实验。秦皮素是评分最高的化合物，具有双重 UA 排泄功能，可降低血清尿酸（SUA）水平。秦皮素通过抑制肝脏黄嘌呤氧化酶（XO）的表达和活性，以及调节肾脏中的 UA 转运体来发挥这些作用。秦皮素抑制 XO 的机制与抑制己糖激酶 2（HK2）的核转位有关。秦皮素通过抑制 TGF-β1 激活的促纤维化信号，在 HUA 和 UUO 小鼠中具有抗纤维化作用。秦皮素在 HUA 小鼠中的肾脏保护作用与较低的 SUA、氧化应激的缓解以及纤维化的抑制有关。秦皮素是一种有潜力的降尿酸药物，具有抑制 XO、促进 UA 排泄、保护氧化应激损伤和减少肾纤维化的作用。
