目的 研究槲皮素对尿酸性肾病大鼠模型的干预作用及其分子机制。方法 设对照组，模型组，槲皮素低、中、高剂量（25、50、100 mg/kg）组和别嘌呤醇（5 mg/kg）阳性对照组。除对照组外，其他组大鼠每天ig给予腺嘌呤100 mg/kg＋乙胺丁醇250 mg/kg 1次，连续给予3周造模。每天给予造模药物后1 h，槲皮素组和别嘌呤醇组ig相应药物1次，连续给药3周。观察大鼠肾脏组织病理学变化，检测血清和尿液中尿酸（Sur和Uur）及肌酐（Scr和Ucr）的水平，检测血清尿素氮（BUN）水平，计算分级尿酸排泄系数（FEUA）；RT-PCR和Western blotting法检测肾脏NOD样受体蛋白3（NLRP3）炎症体各组分NLRP3、细胞凋亡相关斑点样蛋白（ASC）、Caspase-1和TLRs信号通路关键因子Toll样受体2（TLR2）、TLR24基因和蛋白表达。结果 与模型组比较，槲皮素各剂量组和别嘌呤醇组大鼠血清中Sur、Scr水平显著降低，24 h的Uur、Ucr排泄量升高，并能恢复FEUA。模型组大鼠肾脏中NLRP3、ASC、Caspase-1、TLR2、TLR4基因和蛋白表达显著上调，而槲皮素和别嘌呤醇能够逆转上述指标的改变。结论 NLRP3炎症体和TLRs信号通路的激活参与尿酸性肾病的发病过程，槲皮素可通过对其的调控缓解尿酸性肾病。

Objective To investigate the intervention of quercetin on rats with uric acid nephropathy (UAN) and its molecular mechanisms. Methods Rats were divided into six groups including normal, model, quercetin (25, 50, and 100 mg/kg)-treated, and allopurinol (5 mg/kg)-treated groups. Adenine (100 mg/kg) and ethambutol (250 mg/kg) were ig given to rats once daily for consecutive three weeks to establish UAN model. Quercetin (25, 50, and 100 mg/ kg) and allopurinol (5 mg/kg) were initially ig given to UAN rats 1 h after adenine and ethambutol had been given. Rat renal histopathological changes were observed; The levels of uric acid (Sur and Uur), creatinine (Scr and Ucr), and blood urea nitrogen (BUN) in serum and urine were detected; The fractional excretion of uric acid (FEUA) was calculated. Simultaneously, mRNA and protein levels of components of NOD like receptor protein 3 (NLRP3) inflammasomes (NLRP3, ASC, and Caspase-1) and key factors in Toll like receptors (TLRs) signaling pathways (TLR2 and TLR4) were analyzed by RT-PCR and Western blotting methods, respectively. Results Compared with the model group, quecetin and allopurinol reduced Sur and Scr levels significantly, increased Uur and Ucr excretion in 24 h, and recovered FEUA in UAN rats. Moreover, the mRNA and protein expression of NLRP3, ASC, Caspase-1, TLR2, and TLR4 was up-regulated in UAN rat kidneys, which could be reversed by the treatment of quercetin and allopurinol. Conclusion These findings suggest that the activated NLRP3 inflammasomes and TLRs signaling pathways could play the causal roles in UAN pathogenesis. Quercetin could ameliorate UAN by regulating NLRP3 inflammasomes and TLRs signaling pathways.

国家自然科学基金资助项目（NSFC 81202573）；中国药科大学天然药物活性组分与药效国家重点实验室开放课题（SKLNMKF201319）