不同程度肝肾损伤的高尿酸血症大鼠模型研究

Hyperuricemia rat models with various degrees of hepatic and renal injuries

目的筛选稳定的高尿酸血症大鼠模型方法。方法单用或联合氧嗪酸钾、果糖、次黄嘌呤造模,观察不同给药方式和时间制备的高尿酸血症大鼠血清尿酸、肌酐、尿素氮水平、黄嘌呤氧化酶(Xanthine oxidase,XO)、谷草转氨酶(Aspartate aminotransferase,AST)、谷丙转氨酶(Alanine aminotransferase,ALT)活性、肝肾病理切片变化、肾三磷酸腺苷结合转运蛋白G超家族成员2(ATP binding cassette subfamily g member 2,ABCG2)蛋白表达情况。结果与正常组相比,单用氧嗪酸钾造模7 d大鼠血清尿酸、尿素氮水平、AST、XO活力显著上升(P<0.05),肝肾有轻微损伤,肾ABCG2蛋白表达显著下降(P<0.05)。果糖和氧嗪酸钾联合造模7 d大鼠血清尿酸显著升高(P<0.05),血清肌酐、尿素氮水平、AST、ALT、XO活力、肾ABCG2蛋白表达无差异变化(P>0.05),联合造模14 d大鼠血尿酸、尿素氮水平和XO活力显著上升(P<0.05),AST和ALT活力无差异变化(P>0.05),肝肾损伤不显著。次黄嘌呤和氧嗪酸钾联合造模7 d,大鼠血尿酸、肌酐、尿素氮水平、AST、ALT、XO活性显著升高(P<0.05),肝肾损伤严重,肾ABCG2蛋白表达量下降(P<0.05)。结论单用氧嗪酸钾可建立轻微肝肾损伤的急性高尿酸血症模型,果糖联合氧嗪酸钾可建立肝肾损伤小的慢性高尿酸血症模型,次黄嘌呤联合氧嗪酸钾可建立肝肾损伤严重的急性高尿酸血症模型。

Objective To establish a stable rat model of hyperuricemia.Methods By administering potassium oxonate alone or in combination with fructose or hypoxanthine,a hyperuricemia model was established with different administration times using various modeling method.The levels of serum uric acid,creatinine,urea nitrogen,xanthine oxidase(XO),aspartate aminotransferase(AST),and alanine aminotransferase(ALT)activity of hyperuricemia rats were measured.Pathological changes in the liver and kidney were observed.Protein expression of ATP-binding cassette subfamily G member 2(ABCG2)were analyzed.Results Compared with the normal group,the levels of the serum uric acid,urea nitrogen,AST,and XO activity in rats administered potassium oxonate alone for 7 days were increased significantly(P<0.05),while the liver and kidney were slightly injured and kidney ABCG2 protein expression was decreased significantly(P<0.05).Compared with the normal group,the level of serum uric acid in rats was increased significantly(P<0.05),whereas the levels of creatinine,urea nitrogen,AST,ALT,and XO activity and kidney ABCG2 protein expression showed no significant changes(P>0.05)in the group with 7 day of combined potassium oxonate and fructose administration.The levels of serum uric acid,urea nitrogen,and XO activity were increased significantly(P<0.05)and the levels of AST and ALT activity showed no significant changes(P>0.05)in the group with 14 days of potassium oxonate and fructose administration.There were no significant morphological changes in the liver and kidney of rats.Compared with the normal group,the levels of serum uric acid,creatinine,urea nitrogen,and AST,ALT,XO activity in rats with 7 days of potassium oxonate and hypoxanthine administration were increased significantly(P<0.05).Kidney ABCG2 protein expression was decreased significantly(P<0.05)and the damage of the liver and kidneys was severe.Conclusions Potassium oxonate alone was suitable to establish a rat model of acute hyperuricemia with mild hepatic and renal injuries.Fructose combined with potassium oxonate may successfully establish a chronic hyperuricemia rat model with no significant effects on the liver or kidneys.Hypoxanthine combined with potassium oxonate successfully established an acute hyperuricemia rat model with severe hepatic and renal injuries.