沙格列汀通过下调哺乳动物雷帕霉素靶蛋白(mTOR)表达减轻糖尿病大鼠肾损伤

Saxagliptin alleviates kidney injury in diabetic rats by down-regulating the expression of mammalian target of rapamycin(mTOR)

目的探讨沙格列汀(Sax)对糖尿病大鼠肾脏损伤的保护作用及机制。方法SD雄性大鼠14只给予腹腔注射链脲佐菌素(STZ)建立2型糖尿病(T2DM)模型,造模成功后随机分为T2DM组和Sax组,6只大鼠为正常对照(NC)组。Sax组给予Sax溶液灌胃,其余两组灌胃予以等量的羧甲基纤维素钠溶液,8周后处死大鼠,留存血液和肾脏组织。全自动生化分析仪检测血清葡萄糖(Glu)、白蛋白(ALB)、天冬氨酸氨基转移酶(AST)、丙氨酸氨基转移酶(ALT)、血清肌酐(Scr)、血尿素氮(BUN)、尿酸(UA)、血清总胆固醇(TC)、甘油三酯(TG);HE、PAS、Masson染色及透射电镜观察肾脏病变情况;免疫组织化学染色法检测大鼠肾脏哺乳动物雷帕霉素靶蛋白(mTOR)、白细胞介素1(IL-1)、IL-6、肿瘤坏死因子α(TNF-α)的表达和分布。结果与NC组相比,T2DM组大鼠Glu、ALB、AST、ALT、Scr、BUN、UA、TC、TG水平明显升高;肾小球系膜细胞数量增多、系膜基质增厚;mTOR、IL-1、IL-6、TNF-α的蛋白表达水平明显增高。与T2DM组相比,Sax组大鼠Glu、ALB、AST、ALT、Scr、BUN、UA、TC、TG水平降低,肾损伤减轻;mTOR、IL-1、IL-6、TNF-α的表达显著降低。结论Sax可能通过下调mTOR表达,抑制炎症反应,减轻糖尿病大鼠肾损伤。

Objective To investigate the effect of saxagliptin(Sax)against kidney injury in diabetic rats and its mechanisms.Methods SD male rats were fed for 2 weeks,among which 14 rats were selected randomly and given intraperitoneal injection of streptozotocin(STZ)to establish the type 2 diabetes mellitus(T_(2)DM)model,and then were randomly divided into T2DM group and Sax group after the model was successfully established;6 rats were selected as normal control(NC)group randomly.The rats of Sax group were given the saxagliptin solution.The rats of NC and T2DM groups were injected with the same amount of sodium carboxymethyl cellulose solution.After 8 weeks of continuous gastric administration,the rats were sacrificed and their blood and kidney tissues were collected.Glucose(Glu),albumin(ALB),aspartate transaminase(AST),alanine transaminase(ALT),serum creatinine(Scr),blood urea nitrogen(BUN),uric acid(UA),serum total cholesterol(TC),triglycerides(TG)were detected by automatic biochemical analyzer.HE,PAS,Masson staining and transmission electron microscopy were performed to observe the morphological changes of renal.Immunohistochemical staining was used to detect the protein expression level of mammalian target of rapamycin(mTOR),interleukin 1(IL-1),IL-6,tumor necrosis factor a(TNF-a)in renal tissues.Results Compared with the NC group,the levels of biochemical indicators such as Glu,ALB,AST,ALT,Scr,BUN,UA,TC,and TG showed significant increase;the number of glomerular mesangial cells also increased,and the mesangial matrix hyperplasia,mTOR,IL-1,IL-6,TNF-a protein expression levels exhibited significant increase in T_(2)DM group.Compared with T_(2)DM group,Sax group showed decreased levels of biochemical indicators such as Glu,ALB,AST,ALT,Scr,BUN,UA,TC,and TG and improved renal pathological damage performance,together with a profound reduction in mTOR,IL-1,IL-6,TNF-a protein expression level.Conclusion Sax may suppress inflammatory response and reduce renal injury in diabetic rats by down-regulating mTOR expression.