非布司他对高尿酸血症模型大鼠血清尿酸水平和肾组织中NLRP3蛋白表达水平的影响

目的：探讨非布司他对高尿酸血症模型大鼠血清尿酸水平和肾组织中核苷酸结合寡聚化结构域样受体蛋白3（NLRP3）蛋白表达水平的影响，并阐明其作用机制。方法：将45只大鼠随机分为对照组、高尿酸血症组和非布司他组，每组15只。高尿酸血症组和非布司他组大鼠采用氧嗪酸钾灌胃建立高尿酸血症模型，非布司他组大鼠每天给予7.2 mg·kg^-1非布司他，对照组大鼠每天给予等量生理盐水，共4周。HE染色观察各组大鼠肾组织病理形态表现。全自动生化仪测定各组大鼠血清尿酸、肌酐和尿素氮水平，酶联免疫吸附测定（ELISA）法测定各组大鼠血清白细胞介素1β（IL-1β）和白细胞介素18（IL-18）水平，免疫组织化学法测定各组大鼠肾组织中凋亡相关斑点样蛋白（ASC）和NLRP3蛋白表达水平。结果：与对照组比较，高尿酸血症组大鼠尿量和饮水量升高（t=5.317，t=3.674，P<0.05），体质量降低（t=6.374，P<0.05），血清尿酸、肌酐和尿素氮水平升高（t=21.463，t=15.342，t=4.603，P<0.05），血清IL-1β和IL-18水平升高（t=35.761，t=44.168，P<0.05），肾组织中ASC和NLRP3蛋白表达水平升高（t=17.064，t=26.314，P<0.05）；与高尿酸血症组比较，非布司他组大鼠尿量和饮水量降低（t=4.027，t=2.976，P<0.05），体质量升高（t=3.694，P<0.05），血清尿酸、肌酐和尿素氮水平降低（t=13.064，t=7.461，t=3.528，P<0.05），血清IL-1β和IL-18水平降低（t=24.162，t=17.314，P<0.05），肾组织中ASC和NLRP3蛋白表达水平降低（t=8.061，t=11.057，P<0.05）。结论：非布司他可能通过抑制大鼠肾组织中NLRP3炎症小体的激活及其下游炎性因子水平发挥对高尿酸血症模型大鼠的肾脏保护作用。

Effects of febuxostat on serum uric acid level and expression level of NLRP3 protein in kidney tissue in hyperuricemia model rats

Objective: To discuss the effects of febuxostat on the serum uric acid level and the expression level of nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) protein in the hyperuricemia model rats, and to elucidate their mechanisms. Methods: A total of 45 rats were randomly divided into control group, hyperuricemia group and febuxostat group,and there were 15 rats in each group. The rat models of hyperuricemia were established in hyperuricemia group and febuxostat group by intragastric administration of potassium oxonate. The rats in febuxostat group were given a daily dose of 7.2 mg·kg^-1 febuxostat,and the rats in control group were administrated with the same volume of normal saline,lasted for 4 weeks. HE staining was used to observe the pathomorphology of kidney tissue of the rats in various groups, automatic biochemical analyzer was used to detect the levels of serum uric acid, creatinine and urea nitrogen of the rats in various groups,ELISA method was used to determine the levels of serum interleukin-1β (IL-1β) and interleukin-18(IL-18) of the rats in various groups,and immunohistochemistry method was performed to detect the expression levels of apoptosis-associated speck-like protein (ASC) and NLRP3 proteins in kidney tissue of the rats in various groups. Results: Compared with control group, the urine volume and water intake of the rats in hyperuricemia group were increased (t=5.317,t=3.674,P<0.05), the body weight was decreased (t=6.374,P<0.05), the levels of serum uric acid, creatinine and urea nitrogen were increased (t=21.463,t=15.342,t=4.603,P<0.05),the serum IL-1β and IL-18 levels were increased (t=35.761,t=44.168,P<0.05),and the expression levels of ASC and NLRP3 protein in kidney tissue were increased (t=17.064,t=26.314,P<0.05);compared with hyperuricemia group, the urine volume and water intake of the rats in febuxostat group were decreased (t=4.027,t=2.976,P<0.05),the body weight was increased (t=3.694,P<0.05),the serum blood uric acid, creatinine and urea nitrogen levels were decreased (t=13.064,t=7.461,t=3.528,P<0.05),the serum IL-1β and IL-18 levels were decreased (t=24.162,t=17.314,P<0.05),and the expression levels of ASC and NLRP3 protein in kidney tissue were decreased (t=8.061,t=11.057,P<0.05). Conclusion: Febuxostat may play a kidney protective role in the hyperuricemia model rats by inhibiting the activation of NLRP3 inflammatory bodies and the levels of its downstream inflammatory factors.