Zhao Lei, Li Yihang, Yao Dahong, Sun Ran, Liu Shifang, Chen Xi, Lin Congcong, Huang Jian, Wang Jinhui, Li Guang
Department of Medicinal Chemistry and Natural Medicine Chemistry, College of Pharmacy, Harbin Medical University, Harbin, China.
Yunnan Branch, Institute of Medicinal Plant, Chinese Academy of Medical Sciences, Peking Union Medical College, Jinghong, China.
Front Pharmacol. 2021 Nov 8;12:772504. doi: 10.3389/fphar.2021.772504. eCollection 2021.
The prevalence of hyperuricemia is considered high worldwide. Hyperuricemia occurs due to decreased excretion of uric acid, increased synthesis of uric acid, or a combination of both mechanisms. There is growing evidence that hyperuricemia is associated with a decline of renal function. This study is aimed at investigating the effects of the novel compound on lowering the serum uric acid level and alleviating renal inflammation induced by high uric acid in hyperuricemic mice. Hyperuricemic mice model was induced by potassium oxonate and used to evaluate the effects of the novel compound named FxUD. Enzyme-linked immunosorbent assay was used to detect the related biochemical markers. Hematoxylin-eosin (HE) staining was applied to observe pathological changes. The mRNA expression levels were tested by qRT-PCR. The protein levels were determined by Western blot. In parallel, human proximal renal tubular epithelial cells (HK-2) derived from normal kidney was used to further validate the anti-inflammatory effects . FxUD administration significantly decreased serum uric acid levels, restored the kidney function parameters, and improved the renal pathological injury. Meanwhile, treatment with FxUD effectively inhibited serum and liver xanthine oxidase (XOD) levels. Reversed expression alterations of renal inflammatory cytokines, urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) were observed in hyperuricemic mice. Western blot results illustrated FxUD down-regulated protein levels of inflammasome components. Further studies showed that FxUD inhibited the activation of NF-κB signaling pathway in the kidney of hyperuricemic mice. In parallel, the anti-inflammatory effect of FxUD was also confirmed in HK-2. Our study reveals that FxUD exhibits the anti-hyperuricemic and anti-inflammatory effects through regulating hepatic XOD and renal urate reabsorption transporters, and suppressing NF-κB/NLRP3 pathway in hyperuricemia. The results provide the evidence that FxUD may be potential for the treatment of hyperuricemia with kidney inflammation.
高尿酸血症在全球范围内的患病率被认为很高。高尿酸血症的发生是由于尿酸排泄减少、尿酸合成增加或这两种机制共同作用。越来越多的证据表明，高尿酸血症与肾功能下降有关。本研究旨在探讨该新型化合物对降低高尿酸血症小鼠血清尿酸水平及减轻高尿酸诱导的肾脏炎症的影响。通过氧嗪酸钾诱导建立高尿酸血症小鼠模型，用于评估名为FxUD的新型化合物的作用。采用酶联免疫吸附测定法检测相关生化标志物。应用苏木精-伊红（HE）染色观察病理变化。通过qRT-PCR检测mRNA表达水平。通过蛋白质印迹法测定蛋白质水平。同时，使用源自正常肾脏的人近端肾小管上皮细胞（HK-2）进一步验证其抗炎作用。给予FxUD可显著降低血清尿酸水平，恢复肾功能参数，并改善肾脏病理损伤。同时，FxUD治疗有效抑制血清和肝脏黄嘌呤氧化酶（XOD）水平。在高尿酸血症小鼠中观察到肾脏炎性细胞因子、尿酸盐转运蛋白1（URAT1）和葡萄糖转运蛋白9（GLUT9）的表达改变得到逆转。蛋白质印迹结果表明，FxUD下调了炎性小体成分的蛋白质水平。进一步研究表明，FxUD抑制高尿酸血症小鼠肾脏中NF-κB信号通路的激活。同时，FxUD在HK-2中的抗炎作用也得到证实。我们的研究表明，FxUD通过调节肝脏XOD和肾脏尿酸重吸收转运蛋白，并抑制高尿酸血症中的NF-κB/NLRP3途径，发挥抗高尿酸血症和抗炎作用。这些结果提供了证据，表明FxUD在治疗伴有肾脏炎症的高尿酸血症方面可能具有潜力。
