贝前列腺素钠对2型糖尿病大鼠肾P38丝裂原蛋白激酶信号通路的影响

Beraprost sodium inhibits P38MAPK signal pathway in the kidney of type 2 diabetic rats

目的糖尿病肾病是糖尿病常见的慢性并发症之一,是导致终末期肾病的主要原因。观察贝前列腺素钠(商品名:德纳)对2型糖尿病大鼠肾P38丝裂原蛋白激酶(mitogen-activated protein kinase,MAPK)信号通路的影响。方法将30只SD大鼠随机分为正常对照(normal control,NC)组,2型糖尿病(type 2 diabetes mellitus,T2DM)组,贝前列腺素钠治疗组,T2DM组和治疗组大鼠给予高脂饮食合并小剂量链脲菌素(STZ)腹腔注射,建模成功后,治疗组给予0.6 mg/kg/d贝前列腺素钠灌胃,其余饲养条件3组相同,最终纳入实验各组6只。用药8周后检测各组大鼠体重、血糖、24 h尿量、肾重体重比(KW/BW)、24 h尿蛋白(UAlb/24 h),血肌酐(creatinine,Cr),尿素氮(blood urea nitrogen,BUN)。Western blot检测肾皮质组织中p-P38 MAPK、t-P38 MAPK以及TNF-α、TGF-β1、基质金属蛋白酶(matrix metalloproteinase,MMP)-9,环氧化酶-2(cycloxygenase,COX-2)的表达。结果用药8周后,T2DM组血糖、尿量、KW/BW、UAlb/24 h、Cr、BUN水平以及p-P38 MAPK、TNF-α、MMP-9、COX-2蛋白表达均较NC组显著升高;体重较NC组显著降低(P<0.01)。BPS组较T2DM组血糖、UAlb/24 h水平以及p-P38 MAPK、TNF-α、MMP-9、COX-2蛋白表达显著降低(P<0.01),尿量、KW/BW、Cr水平以及TGF-β1蛋白表达有所降低(P<0.05),体重有所升高(P<0.05)。结论贝前列素钠可抑制肾P38MAPK信号通路以及相关炎性因子(TNF-α、COX-2等)的表达水平,对T2DM大鼠肾具有明显的保护作用。

Objective Diabetic nephropathy is one of the most common chronic complications of diabetes mellitus as well as a leading cause of end-stage renal disease. This study was to observe the effect of beraprost sodium （BPS） on the P38 mitogen-activated protein kinase （P38MAPK） signal pathway in the kidney of type 2 diabetic rats. Methods Thirty SD rats were randomly divided into a control, a type 2 diabetes （T2D） , and a BPS treatment （BPS）. The latter two groups received high-fat diet and low-dose streptozotocin to make T2D models, and then the rats of the BPS group were treated by intragastric administration of BPS at 0.6 mg/kg per day. At last, 6 were selected from each group for this study. After 8 weeks of treatment, we examined the body weight （BW）, kidney weight （KW）, KW/BW ratio, blood glucose （BG）, 24 h urinary albumin （UAlb/24 h）, creatinine （Cr） and blood urea nitrogen （BUN） of all the rats, and detected the expressions of p-P38MAPK, t-P38MAPK, TNF-α, TGF-IM, MMP-9 and COX-2 in the renal cortical tissue by Western blot. Results After 8 weeks of treatment, the T2D group showed significant increases in BG, KW/BW ratio, UAlb/24 h, Cr, BUN and expressions of p-P38 MAPK, TNF-α, MMP-9 and COX-2, but a markedly decreased BW as compared with the control rats （ P 〈 0.01 ）. In comparison with the T2D rats, the rats in the BPS group exhibited significant decreases in BG, UAlb/24 h and expressions of p-P38 MAPK, TNF-α, MMP-9 and COX-2 than the T2D group （P 〈0.01 ）, as well as in KW/BW ratio, Cr and TGF-β1 expression （P 〈 0.05 ）, but a remarkable increase in BW （ P 〈 0.05 ）. Conclusion BPS can inhibit the P38MAPK signal pathway and the expressions of inflammatory factors, such as TNF-α and COX-2, and plays a protective role in type 2 diabetic rats with nephropathy.