Notch通路在高浓度葡萄糖腹膜透析液所致大鼠腹膜纤维化模型中的活化  

Notch activity is increased in a rat peritoneal fibrosis model induced by high glucose dialysate

作　　者：朱风新[1] 聂静[1] 孙旸[1] 邱芳华[1] 刘伟[1] 伍巧源[1] 毛海萍[1] 关伟明[1] 彭文兴[1] 余学清[1] 

机构地区：[1]中山大学附属第一医院肾内科,广州510080

出　　处：《中华肾脏病杂志》2008年第6期411-416,共6页Chinese Journal of Nephrology

基　　金：国家自然科学基金（30570942）

摘　　要：目的观察Notch通路在高浓度葡萄糖透析液所致大鼠腹膜纤维化模型中的变化并探讨其可能机制。方法给予sD雄性大鼠每日腹腔注射高浓度葡萄糖腹膜透析液，于实验后2周和4周杀检。取壁层腹膜组织行光镜检查；免疫印迹检测转化生长因子β1（TGF—β1）、E钙黏蛋白（E-cadherin）、α平滑肌肌动蛋白（α-SMA）和Ⅰ型胶原蛋白（ColⅠ）的表达；RT-PCR检测Notch通路的下游靶基因Hes-1的表达；免疫印迹和RT．PCR检测Notch配体Jagged-1和Notch通路的负性调节因子Numb的表达。结果HE染色显示模型组腹膜明显增厚，间皮细胞减少；Masson染色显示壁层腹膜中可见明显的胶原沉积。与健康对照组相比，模型组的TGF-β1、α-SMA和ColⅠ的表达增加而E-cadherin的表达下降（均P〈0．01）。4周模型组与对照组相比Jagged-1表达明显增加（P〈0．05），同时Hes-1的表达亦明显增加（P〈0.01），而Notch通路的负性调节因子Numb的表达下降（P〈0．01）。结论在高浓度葡萄糖腹膜透析液所致的大鼠腹膜纤维化模型中有Notch通路的活化，而该通路的活化可能与Notch通路的负性调节因子Numb表达的下调有关。高表达Notch通路的负性调节因子，如Numb，可能是治疗腹膜透析患者腹膜纤维化的新途径。Objective To investigate the role of Notch signaling in the progression of peritoneal fibrosis in a rat model induced by high glucose dialysate. Methods Male Sprague Dawley rats were subjected to daily peritoneal dialysis （PD） with a lactate-buffered solution containing 4.25% glucose. They were sacrificed at 2 and 4 weeks after PD. The parietal thickness was measured with Masson staining. The expression of TGF-β1, E-cadherin, α-SMA and collagen I was examined by immunoblotting. The expression of Notch ligand Jagged-1 and the negative Notch signaling regulator Numb was analyzed by both immunoblotting and RT-PCR. The expression of a Notch nuclear target gene Hes-1 was examined by RT-PCR. Results Both HE and Masson trichrome staining revealed an increase in peritoneal thickness with a loss of mesothelial cells and a rich of collagen matrix deposition in the submesothelial zone was evident at 4 weeks after PD. Meanwhile, compared to healthy rats, the expression of TGF-β1, α-SMA and collagen I was significantly increased, but the expression of E-cadherin was decreased in peritoneum after PD treatment. It was difficult to detect the Jagged-1 and Hes-1 expression in normal peritoneum, but their expression was gradually increased after PD. In contrast, the expression level of Numb, a negative regulator of Notch signaling, was dramatically decreased after PD. Conclusions Notch signaling is activated during the process of PD-induced peritoneal fibrosis and the activation of Notch signaling is associated with the loss of negative regulation of Notch signaling via decreased expression of Numb. Inhibition of Notch signaling via overexpression of its negative regulators such as Numb may be a novel therapeutic approach for peritoneal fibrosis in PD patients.

关 键 词：腹膜透析 透析液 转化生长因子Β NOTCH通路 NUMB 

分 类 号：R692.5[医药卫生—泌尿科学]