替米沙坦抑制Mtdh表达激活自噬在改善腹膜纤维化中的作用  

Telmisartan ameliorates peritoneal fibrosis by suppressing metadherin and activating autophagy

作　　者：王育娴 李淑婷 陈斯佳 罗丛伟 龙海波[2] 彭芬芬[2] WANG Yuxian;LI Shuting;CHEN Sijia;LUO Cuowei;LONG Haibo;PENG Fenfen(Department of Gerontology,Zhujiang Hospital,Southern Medical University,Guangzhou 510280,China;Department of Nephrology,Zhujiang Hospital,Southern Medical University,Guangzhou 510280,China;Department of Nephropathy&Rheumatology,The First Hospital of Changsha,Changsha 410000,China)

机构地区：[1]南方医科大学珠江医院老年医学科,广州510280 [2]南方医科大学珠江医院肾内科,广州510280 [3]长沙市第一医院肾病风湿科

出　　处：《肾脏病与透析肾移植杂志》2022年第1期39-44,共6页Chinese Journal of Nephrology,Dialysis & Transplantation

基　　金：国家自然科学基金(81873346、U1801288、81900607、82071563、82000682)。

摘　　要：目的:探究替米沙坦对腹膜透析相关性腹膜纤维化的影响及异黏蛋白metadherin(Mtdh)和自噬在其中的作用。方法:采用4.25%葡萄糖腹膜透析液建立小鼠腹膜透析相关性腹膜纤维化模型和转化生长因子β1(TGF-β1)诱导的腹膜间皮细胞间质转分化模型。C57BL/6J小鼠按体重随机分为对照组、模型组及替米沙坦干预组;Masson染色观察腹膜厚度变化;免疫组织化学染色和Western Blot检测纤维连接蛋白(Fib)、Ⅰ型胶原蛋白(ColⅠ)、E-钙黏蛋白(E-cadherin)、TGF-β1、Mtdh、微管相关蛋白轻链3(LC3A/B)的表达。体外人腹膜间皮细胞利用siRNA下调Mtdh表达并予TGF-β1刺激,Western Blot检测上述蛋白的表达情况。结果:与对照组对比,模型组小鼠壁层腹膜厚度明显增厚,纤维化显著加重,Fib、ColⅠ、TGF-β1、Mtdh表达水平明显升高、E-cadherin、LC3A/B-Ⅱ表达降低,替米沙坦可减轻小鼠腹膜纤维化程度、下调Mtdh表达,并上调LC3A/B-Ⅱ的表达。体外下调Mtdh表达后,LC3A/B-Ⅱ表达升高,ColⅠ表达降低。结论:替米沙坦可抑制Mtdh表达,增强自噬水平,从而改善腹膜纤维化。Objective:To explore effect of telmisartan in a mouse model of peritoneal fibrosis,role of metadherin(Mtdh)and autophagy in this model were studied.Methodology:A mouse peritoneal fibrosis model was established by daily intraperitoneal injection of 3 ml of 4.25%glucose dialysate for 28 days.Eighteen C57 BL/6 J mice were randomized into control group,model group and telmisartan treatment group.Masson staining was used to observe peritoneal thickness;immunohistochemical staining and Western Blot were used to detect expression of Fibronectin(Fib),CollagenⅠ(ColⅠ),E-cadherin,TGF-β1,Mtdh and LC3 A/B in each group.In the vitro experiment,human peritoneal mesothelial cell line(HMrSV5 cells)was stimulated with TGF-β1 and transfected with a siRNA targeting Mtdh,expressions of extracellular matrix proteins,LC3 A/B and Mtdh were detected with Western blotting.Results:Compared with control mice,mice exposed to peritoneal dialyate showed increased thickening of peritoneal membrane within the anterior abdominal wall,accompanied by elevated levels of Fib,ColⅠ,TGF-β1,Mtdh,decreased levels of E-cadherin and LC3 A/B-Ⅱ.While in telmisartan treated mice,the peritoneal thickness was reduced,and expression of Fib,ColⅠ,TGF-β1,Mtdh were significantly suppressed,and the expression of E-cadherin,LC3 A/B-Ⅱwere significantly increased.In vitro,siRNA-mediated knockdown of Mtdh obviously reversed TGF-β1 induced expressions of ColⅠand Mtdh,accompanied by upregulation of LC3 A/B-Ⅱ.Conclusion:Telmisartan can inhibit Mtdh expression,promote autophagy and ameliorate peritoneal fibrosis.

关 键 词：替米沙坦 自噬 腹膜纤维化 

分 类 号：R965[医药卫生—药理学]