Ⅱ型糖尿病大鼠白内障的ERK通路介导机制及其抑制剂PD98059的改善作用

Involvement of ERK pathway in cataract in type Ⅱ diabetes and alleviations of PD98059, inhibitor of ERK

目的分析ERK通路在Ⅱ型糖尿病大鼠白内障发生中的参与机制及PD98059的改善作用。方法 35只SD大鼠随机分为对照组、糖尿病组、PD98059低剂量、中剂量和高剂量组(每组7只)。小剂量STZ联合高糖高脂饮食120 d复制糖尿病大鼠白内障模型,第64天每天对各组大鼠尾静脉注射生理盐水或PD98059。分析各组大鼠晶状体状态及胰岛素抵抗系数HOMA-IR的变化,Real-time PCR和Western blotting分析晶状体中ERK通路相关蛋白ERK1/2、p-ERK1/2、p38及内质网应激蛋白ATF6、PERK的表达变化。结果与对照组大鼠比较,糖尿病组大鼠晶状体明显浑浊,HOMA-IR明显增高,晶状体组织中p-ERK1/2、p38、PERK和ATF6表达上调,而总ERK的表达未发生变化。PD8059可以显著改善上述晶状体及相关蛋白表达的异常,且具有剂量依从性。结论激活的ERK信号通路参与了Ⅱ型糖尿病大鼠白内障发病过程,PD95059通过抑制上调表达的p38-p ERK1/2及内质网应激起缓解作用。

Objective To explore the involvement of ERK pathway in the pathogenesis of typeⅡdiabetic cataract and the interventions of PD98059 （the inhibitor of ERK）. Methods Thirty-five male SD rats were divided in-to five groups：control group, diabetic group, low/middle/high dose of PD98059 group （n=7 in each group）. The typeⅡdiabetic cataract model was duplicated by low dose of STZ injections combined with high content of fat and sugar diet for 120 d. All the rats were administrated with normal saline or PD98059. The HOMA-IR was calculated in each group. And at the same time, the expression of ERK1/2, p-ERK1/2, p38, ATF6 and PERK were detected by Western blotting or real-time PCR. Results The HOMA-IR in diabetic group was increased greatly with cloudy lens when compared to the control group. The expression of p-ERK1/2, p38, ATF6 and PERK were up-regulated dramatically in diabetic group, while the expression of total ERK has no change. PD98059 alleviated the cloudy lens in diabetic rats significantly and normalized the aforementioned abnormal proteins greatly. Conclusion Activated ERK pathway and endoplasmic reticulum stress are involved in the pathogenesis of cataract in typeⅡdiabetes. PD98059 alleviates the cataract by inhibiting the aforementioned parameters in a dose dependent manner.