东革阿里叶提取物调节肾脏尿酸转运体改善高尿酸血症作用研究

Eurycoma longifolia jack leaf extract alleviates hyperuricemia by regulating renal urate transporters

关键词:  东革阿里叶提取物  高尿酸血症  尿酸盐转运体  肾脏排泄

Key words:  Eurycoma longifolia jack leaf extract  hyperuricemia  urate transporter  renal excretion

摘要:

[目的] 探究东革阿里叶提取物（ELL）调节高尿酸血症的药效及作用机制。[方法] 采用氧嗪酸钾联合腺嘌呤连续给药3周建立高尿酸血症小鼠模型，每周采血检测血清尿酸及肌酐水平；末次取材前装入小鼠代谢笼，收集24 h尿液，检测尿液尿酸水平并计算尿酸清除率（Cur）；对肾脏进行苏木精-伊红（HE）染色分析肾脏组织病理情况；采用实时荧光定量聚合酶链式反应（RT-PCR）、蛋白免疫印迹（Western blot）法研究肾脏中尿酸转运相关基因及蛋白表达情况。[结果] 随着高尿酸血症病情加重，小鼠体质量较正常组逐渐降低，饮食量减少而饮水量增加，ELL能够在200 mg/kg以上剂量下恢复体质量增长；造模1周后小鼠血清尿酸水平随即升高，且随着造模时间的增长尿酸清除率显著降低，ELL治疗后血尿酸与血肌酐水平显著降低，同时尿酸清除率与肌酐清除率明显上升；ELL还能够缓解肾脏病理损伤，改善肾脏功能；RT-PCR与Western blot结果表明ELL能够下调肾脏尿酸盐阴离子转运蛋白1（URAT1）和葡萄糖转运体9（GLUT9）的表达，上调有机阴离子转运体（OAT1）、钠-磷协同转运体1（NPT1）以及磷酸腺苷结合盒式蛋白超家族2（ABCG2）的表达。[结论] ELL能够有效降低伴肾功能损伤的高尿酸血症模型小鼠的血尿酸水平，其作用机制主要与调节肾脏尿酸转运体、抑制重吸收并促进排泄有关。

Abstract:

[Objective] To investigate the therapeutic efficacy and underlying mechanisms of Eurycoma longifolia jack leaf extract（ELL）in regulating hyperuricemia. [Methods] A mouse model of hyperuricemia was established via continuous 3-week co-administration of potassium oxonate and adenine. Serum uric acid（SUA）and creatinine levels were monitored weekly. Mice were placed in metabolic cages 24 h before sacrifice to collect urine for uric acid quantification and calculation of uric acid clearance（Cur）. Renal histopathology was assessed by HE staining. RT-PCR and Western blot were employed to analyze the expression of urate transporter-related genes and proteins in kidney tissues. [Results] Progressive hyperuricemia led to decreased body weight，reduced food intake，and increased water consumption compared with normal controls. ELL at a dose of more than 200 mg/kg restored weight gain. After 1 week of modeling，SUA levels surged，accompanied by increased urine volume but decreased uric acid excretion. Cur declined significantly over time. ELL treatment markedly reduced SUA and serum creatinine while elevating Cur and creatinine clearance rate（Ccr）. HE staining revealed that ELL alleviated renal pathological damage and improved kidney function. Molecular analyses demonstrated that ELL downregulated renal URAT1 （urate-anion transporter 1）and GLUT9（glucose transporter 9）expression while upregulating OAT1（organic anion transporter 1），NPT1（Na-dependent phosphate cotransporter 1），and ABCG2（ATP-binding cassette superfamily G member 2）. [Conclusion] ELL lowered SUA levels in hyperuricemia mice by enhancing Cur and Ccr and protected renal tissue. The mechanism involved dual modulation of urate transporters：inhibiting reabsorption via downregulation of URAT1/GLUT9 and promoting excretion via upregulation of NPT1/OAT1/ABCG2.