来氟米特活性代谢产物A771726对高糖诱导足细胞凋亡的抑制作用  

Inhibition of leflunomide active metabolite A771726 on high glucose-induced podocyte apoptosis

作　　者：苑玉聪[1] 于为民[1] 李荣山[1] 乔晞[1] 

机构地区：[1]山西医科大学第二医院肾内科山西省肾脏病研究所,太原030001

出　　处：《中华医学杂志》2011年第10期703-706,共4页National Medical Journal of China

基　　金：山西省科技攻关项目（20100311098-3）

摘　　要：目的观察来氟米特活性代谢产物A771726对高糖诱导足细胞凋亡的影响，探讨来氟米特对足细胞损伤的保护作用及可能的机制。方法条件永生的人肾小球足细胞系分为正常糖组、高糖组、甘露醇高渗对照组、高糖＋SB202190[p38丝裂原激活蛋白激酶（MAPK）通路特异性抑制剂]组及高糖＋A771726（来氟米特活性代谢产物）组。Western印迹法检测足细胞p38MAPK及磷酸化p38MAPK（P-p38）活性；流式细胞仪检测足细胞凋亡率。结果（1）高糖刺激足细胞激活p38MAPK信号通路，p-p38蛋白表达明显增加，正常糖组和高渗对照组仅有少量p38活化；SB202190组及A771726组p-p38蛋白表达量较高糖组明显下降。（2）流式细胞仪检测到高糖刺激足细胞24h后可见细胞凋亡增加，48h凋亡最为明显，为（18．6±0．7）％，显著高于正常糖及高渗对照组；SB202190组及A771726组足细胞凋亡率较高糖组分别下降26％和17％，差异有统计学意义。结论来氟米特活性代谢产物A771726能够减少高糖所致的足细胞凋亡，机制可能与其抑制p38MAPK活化相关。Objective To explore the therapeutic effects of leflunomide metabolite A771726 on high glucose-induced podocyte injury and understand its mechanism. Methods The conditionally immortal human glomeroular podocytes were divided into nomal glucose group （ NG ）, high glucose group （ HG）, mannitol group （MA）, high glucose with SB202190 （a p38MAPK inhibitor） group and high glucose with active leflunomide metabolite A771726 group. The levels of p38MAPK and p-p38 protein were determined by Western blot. And the rate of podocyte apoptosis was evaluated by flow cytometry. Results （ 1 ） Podocytes with high glucose could activate the p38MAPK signaling pathway. The p-p38 protein expression was significantly elevated. Little activation of the pathways was observed in Groups NG and MA. As compared to HG, the p-p38 protein expression was significantly lowered in SB202190 and A771726 groups. （2） Apoptosis increased in podocytes with high glucose after 24 h. The apoptotic rate of group HG was the most dramatic at 48 h（ 18.6 ±0. 7） %. It was significantly higher than those of Groups NG and MA. The group of high glucose with SB202190 and high glucose with active leflunomide metabolite A771726 could reduce the podocyte apoptosis by 26% and 17% respectively versus the HG group. And the difference was statistically significant. Conclusion Leflunomide can inhibit high glucose-induced podocyte apoptosis. And this effect may be involved in its inhibition of activation of p38MAPK.

关 键 词：足细胞 凋亡 P38丝裂原活化蛋白激酶类 来氟米特 高糖 

分 类 号：R965[医药卫生—药理学]