氯沙坦抑制转录因子GADDl53/CHOP的激活在糖尿病大鼠肾脏中的保护作用

目的探讨血管紧张素Ⅱ受体1拮抗剂氯沙坦对糖尿病大鼠肾脏细胞凋亡及转录因子GADDl53/CHOP表达的影响。方法单侧肾切除大鼠腹腔注射链脲佐菌素诱发糖尿病,每日灌胃给予氯沙坦(40 mg.kg-1)共8周。应用免疫组织化学检测细胞增殖核抗原(Proliferating cell nuclear anti-gen,PCNA)、GRP78和转录因子GADDl53/CHOP的表达与定位,TUNEL染色检测细胞凋亡部位,流式细胞术检测细胞凋亡程度,并对GRP78、GADDl53/CHOP表达水平进行半定量分析,同时观察尿蛋白、BUN、Scr、Ucr等反应肾功能的相关指标。结果建模8周,糖尿病组大鼠较对照组肾小球、肾小管凋亡细胞数明显增多,GRP78、GADDl53/CHOP表达增强。氯沙坦治疗组较糖尿病组凋亡细胞数减少,GRP78表达减弱,明显抑制GADDl53/CHOP的表达。3组间PCNA阳性细胞数无差异。结论氯沙坦部分通过影响内质网应激中GADDl53/CHOP凋亡途径减少肾脏细胞凋亡,从而发挥肾脏保护作用。

Losartan provides protection on the kidney of diabetic rats by inhibiting the expression of GADDl53/CHOP

Aim To investigate the influence of angiotensinⅡ receptor 1 antagonosm losartan on apoptosis and the expression of GADDl53/CHOP in the kidney of diabetic rats.Methods Intraperitoneal injection of STZ(65 mg·kg-1) was used to induce diabetes in uninephrectomized Wistar rats.Losartan(40 mg·kg-1) was administered daily by gavage from the next day of the induction to diabetes for 8 weeks.The expression and distribution of Proliferating cell nuclear antigen(PCNA),GRP78,GADDl53/CHOP was examined by immunohistochemistry.Flow cytometry was used to detect the levels of protein of GRP78 and GADDl53/CHOP.Apoptosis was evaluated by means of TUNEL and Flow cytometry.Ucr,Scr,BUN and 24-hour urine protein excretion were checked,meanwhile,creatinine clearance rate was detected.Results Compared with those in normal control group,the numbers of apoptosis and the expression of GRP78,GADDl53/CHOP in glomerular and tubular cells were much higher in the diabetic kidneys in 8 weeks.After losartan treatment,decrements were found in the expression of GRP78;GADDl53/CHOP and the numbers of apoptotic cells.While there is no significant difference in the number of PCNA protein among three groups.Conclusion Inhibition of apoptosis and regulation of endoplasmic reticulum stress might be responsible for the renal protective effects of losartan on uninephrectomized Wistar rats with diabetes.