基于TGF-β_(1)/Smad信号通路探究度拉糖肽对2型糖尿病肾病大鼠肾损伤的影响及机制

Effect and Mechanism of Dulaglutide on Kidney Injury in Rats with Type 2 Diabetic Nephropathy Based on the TGF-β_(1)/Smad Signaling Pathway

目的:探讨基于转化生长因子-β(TGF-β_(1))/Smad信号通路度拉糖肽(Dula)对2型糖尿病肾病(T2DN)大鼠肾损伤的影响。方法:随机选取10只大鼠作为Control组,其余大鼠构建T2DN模型,将建模成功的大鼠随机分为T2DN组、L-Dula、M-Dula、H-Dula,Dula+SRI-011381每组10只。测定各组大鼠体质量;采用全自动生化分析仪检测T2DN大鼠血清中ALB、Scr、BUN、TG、TC含量;HE和PAS染色观察T2DN大鼠肾组织病理改变;Western blot检测T2DN大鼠肾组织中TGF-β_(1)、Smad2/3、Smad7蛋白的表达。结果:T2DN组肾小球肥大,基底膜增厚,囊腔萎缩,间质炎性细胞浸润,肾小球内糖原沉积增多,可见红色染色区域,24h尿蛋白、Scr、BUN、FBG、TG、TC、TGF-β_(1)、Smad2/3表达高于Control组,体质量、Smad7表达低于Control组(P<0.05);L-Dula、M-Dula、H-Dula组肾小球和肾小管病变程度均依次减轻,红色染色区域依次减少,24h尿蛋白、Scr、BUN、FBG、TG、TC、TGF-β_(1)、Smad2/3表达低于T2DN组,体质量、Smad7表达高于T2DN组(P<0.05);Dula+SRI-011381组肾小球和肾小管病变加重、红色染色区域增大、24h尿蛋白、Scr、BUN、FBG、TG、TC、TGF-β_(1)、Smad2/3表达高于H-Dula组,体质量、Smad7表达低于H-Dula组(P<0.05)。结论:Dula可能通过抑制TGF-β_(1)/Smad信号通路抑制T2DN大鼠肾损伤。

Objective:To investigate the effect of dulaglutide(Dula)on kidney injury in rats with type 2 diabetic nephropathy(T2DN)and explore the underlying mechanism based on the transforming growth factor-β_(1)(TGF-β_(1))/Smad signaling pathway.Methods:A total of 10 rats were randomly selected as the Control group,while the remaining rats were used to establish a T2DN model.Successfully modeled rats were divided into five groups:T2DN group,L-Dula group(low-dose Dulaglutide),M-Dula group(medium-dose Dulaglutide),H-Dula group(high-dose Dulaglutide),and Dula+SRI-011381 group,with 10 rats per group.The body weight of each group was measured.Serum levels of albumin(ALB),serum creatinine(Scr),blood urea nitrogen(BUN),triglycerides(TG),and total cholesterol(TC)were detected using an automatic biochemical analyzer.Hematoxylin-eosin(HE)and periodic acid-Schiff(PAS)staining were employed to observe pathological changes in kidney tissues.Western blotting was used to detect the expression of TGF-β_(1),Smad2/3,and Smad7 proteins in the kidney tissue of T2DN rats.Results:In the T2DN group,glomerular hypertrophy,thickened basement membranes,shrunken cavities,inflammatory cell infiltration in the interstitial region,and increased glycogen deposition in the glomeruli were observed.Red-stained areas were visible,and the levels of 24-hour urinary protein,Scr,BUN,fasting blood glucose(FBG),TG,TC,TGF-β_(1),and Smad2/3 were significantly higher,while body weight and Smad7 expression were lower than in the Control group(P<0.05).The severity of glomerular and tubular lesions decreased progressively from the L-Dula to the H-Dula group,with a reduction in red-stained areas.Levels of 24-hour urinary protein,Scr,BUN,FBG,TG,TC,TGF-β_(1),and Smad2/3 were lower in the Dula-treated groups compared to the T2DN group,and body weight and Smad7 expression were higher(P<0.05).In the Dula+SRI-011381 group,glomerular and tubular damage worsened,with larger red-stained areas,higher levels of 24-hour urinary protein,Scr,BUN,FBG,TG,TC,TGF-β_(1),and Smad2/3,and lower body weight and Smad7 expression compared to the H-Dula group(P<0.05).Conclusion:Dulaglutide may inhibit kidney injury in T2DN rats by suppressing the TGF-β_(1)/Smad signaling pathway.