Mangiferin Ameliorates Hyperuricemic Nephropathy Which Is Associated With Downregulation of AQP2 and Increased Urinary Uric Acid Excretion
Mangiferin Ameliorates Hyperuricemic Nephropathy Which Is Associated With Downregulation of AQP2 and Increased Urinary Uric Acid Excretion
复制标题
芒果苷可改善与 AQP2 下调和尿酸排泄增加相关的高尿酸血症肾病
DOI：
10.3389/fphar.2020.00049
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发表时间：
2020-02-07
影响因子：
5.6
通讯作者：
Ye, Fei
中科院分区：
文献类型：
--
作者：
Li, Xuechen;Yan, Zhenxin;Ye, Fei
高尿酸血症的特点是血液中循环尿酸水平异常高，与肾损伤风险增加有关。导致高尿酸血症肾病（HN）的病理生理机制包括氧化应激、内皮功能障碍、炎症和纤维化。芒果苷是一种具有生物活性的c -葡萄糖苷类山酮，对多种疾病具有抗炎、抗纤维化和抗氧化作用。本研究旨在评价芒果苷治疗HN的效果。在小鼠HN模型中，我们观察到芒果苷治疗降低了循环尿酸水平，改善了肾功能，这与肾脏炎症和纤维化的减少有关。进一步探讨了芒果苷降低尿酸的作用机制。代谢笼实验表明，给药小鼠由于尿量增加，尿尿酸明显增加，但尿尿酸浓度无明显变化。western blot进一步检测水通道和尿酸转运蛋白的表达。肾AQP2表达降低，而尿酸转运蛋白URAT1、GLUT9和OAT1的表达不受芒果苷的影响。此外，芒果苷处理还能使HN小鼠黄嘌呤氧化酶和SOD活性恢复正常，从而分别降低尿酸合成和改善氧化应激。因此，我们的研究结果揭示了芒果苷通过促进aqp2相关尿酸排泄来降低血清尿酸水平的新机制。这项研究表明芒果苷可能是一种多靶点的候选治疗药物，通过增加排泄和减少尿酸的产生以及调节炎症、纤维化和氧化途径的机制来预防HN。
Hyperuricemia is characterized by abnormally high level of circulating uric acid in the blood and is associated with increased risk of kidney injury. The pathophysiological mechanisms leading to hyperuricemic nephropathy (HN) involve oxidative stress, endothelial dysfunction, inflammation, and fibrosis. Mangiferin is a bioactive C-glucoside xanthone, which has been exerting anti-inflammatory, anti-fibrotic, and antioxidative effects in many diseases. This study aimed to evaluate the effect of mangiferin treatment in HN. In a mouse model of HN, we observed lower circulating urate levels and ameliorated renal dysfunction with mangiferin treatment, which was associated with reduced renal inflammation and fibrosis. We next investigated the mechanism of urate lowering effect of mangiferin. Metabolic cage experiment showed that mangiferin-administrated mice excreted significantly more urinary uric acid due to elevated urine output, but no marked change in urine uric acid concentration. Expressions of water channels and urate transporters were further assessed by western blot. Renal AQP2 expression was decreased, yet urate transporters URAT1, GLUT9, and OAT1 expressions were not affected by mangiferin in HN mice. Moreover, mangiferin treatment also normalized xanthine oxidase and SOD activity in HN mice, which would decrease uric acid synthesis and improve oxidative stress, respectively. Therefore, our results reveal a novel mechanism whereby mangiferin can reduce serum uric acid levels by promoting AQP2-related urinary uric acid excretion. This study suggested that mangiferin could be a multi-target therapeutic candidate to prevent HN via mechanisms that involve increased excretion and decreased production of uric acid and modulation of inflammatory, fibrotic, and oxidative pathways.