四逆汤对慢性肾功能衰竭大鼠尿酸水平及p38 MAPK/ERK1/2信号通路的影响

Effects of Sini decoction on uric acid level and p38 MAPK/ERK1/2 signal pathway in rats with chronic renal failure

目的探究四逆汤对慢性肾功能衰竭(CRF)大鼠血尿酸(UA)水平及p38丝裂原活化蛋白激酶(p38 MAPK)/细胞外信号调节激酶1/2(ERK1/2)信号通路的影响。方法2020年10月—2021年1月于山东第一医科大学附属青岛医院动物实验室进行实验。将72只雄性SD大鼠按随机数字表法分成对照组、模型组、氯沙坦组(9 mg/kg)及四逆汤低、中、高剂量组(2.79、5.58、11.16 g/kg),每组12只。除对照组外,其余各组构建CRF大鼠模型,并给予相应药物处理。测定各组大鼠肾脏指数,血清尿素氮(BUN)、肌酐(SCr)、UA水平,血清炎性因子白介素-6(IL-6)、IL-1β、肿瘤坏死因子-α(TNF-α)水平,观察肾组织病理学变化、细胞凋亡,比较肾组织p38 MAPK、磷酸化p38 MAPK(p-p38 MAPK)、ERK1/2、磷酸化ERK1/2(p-ERK1/2)蛋白表达。结果与对照组比较,模型组大鼠肾脏指数、血清BUN、SCr、UA、IL-6、IL-1β、TNF-α水平及肾组织细胞凋亡指数、p-p38 MAPK/p38 MAPK、p-ERK1/2/ERK1/2蛋白水平均显著升高(P<0.05);与模型组比较,氯沙坦组和四逆汤各剂量组上述指标均显著降低,四逆汤低、中、高剂量组均依次降低(F/P=65.365/0.000、64.573/0.000、100.391/0.000、42.909/0.000、284.425/0.000、108.117/0.000、96.423/0.000、187.402/0.000、67.154/0.000、76.286/0.000)。对照组大鼠肾组织无明显病变;模型组大鼠肾小球结构紊乱、肾小球基底膜增厚、肾小管间质水肿、大量炎性细胞浸润,氯沙坦组和四逆汤各剂量组可明显减轻肾损害和炎性反应,尤其是高剂量组。结论四逆汤可减少CRF大鼠的UA水平,改善肾脏病理变化,可能与抑制p38 MAPK/ERK1/2信号通路活化有关。

Objective To explore the effects of Sini decoction on blood uric acid(UA)level and p38 mitogen activated protein kinase(p38 MAPK)/extracellular signal regulated kinase 1/2(ERK1/2)signal pathway in rats with chronic renal failure(CRF).Methods From October 2020 to January 2021,the experiment was conducted in the animal laboratory of Qingdao Hospital affiliated to Shandong First Medical University.72 male SD rats were randomly divided into control group,model group,losartan group(9 mg/kg)and Sini decoction low,medium and high dose groups(2.79,5.58 and 11.16 g/kg),with 12 rats in each group.In addition to the control group,CRF rat models were constructed in other groups and treated with corresponding drugs.The renal index,serum urea nitrogen(BUN),creatinine(SCr),UA,serum inflammatory factors interleukin 6(IL-6)and IL-1βwere measured,Tumor necrosis factor-α(TNF-α).The expression of p38 MAPK,phosphorylated p38 MAPK(P-p38 MAPK),ERK1/2 and phosphorylated ERK1/2(P-ERK1/2)were compared.Results Compared with the control group,the renal index,serum BUN,SCR,UA,IL-6 and IL-1βin the model group,TNF-α.The levels of p-p38 MAPK/p38 MAPK and p-ERK1/2/ERK1/2 protein was significantly increased(P<0.05);Compared with the model group,the above indexes were significantly decreased in losartan group and Sini decoction groups,and decreased in Sini decoction low,medium and high dose groups in turn(F/P=65.365/0.000,64.573/0.000,100.391/0.000,42.909/0.000,284.425/0.000,108.117/0.000,96.423/0.000,187.402/0.000,67.154/0.000 and 76.286/0.000).In the control group,there was no obvious lesion in renal tissue;The model group had glomerular structural disorder,glomerular basement membrane thickening,renal tubulointerstitial edema and a large number of inflammatory cell infiltration.Losartan group and Sini decoction groups could significantly reduce renal damage and inflammatory reaction,especially in the high-dose group.Conclusion Sini decoction can reduce UA level and improve renal pathological changes in CRF rats,which may be related to inhibiting the activation of p38 MAPK/ERK1/2 signal pathway.