血管紧张素Ⅱ1型受体拮抗剂对糖尿病肾病大鼠肾小球内12-脂氧合酶活性及P钙黏蛋白表达的影响  

Effect of angiotensin II type 1 receptor blocker on the 12-lipoxygenase activity and P-cadherin expression in type 2 diabetic rat glomeruli

作　　者：王婉宁[1] 李佳[1] 马福哲[1] 孙韬[1] 孙珉丹[1] 许钟镐[1] 

机构地区：[1]吉林大学白求恩第一医院肾病内科,长春130021

出　　处：《中华肾脏病杂志》2013年第3期210-215,共6页Chinese Journal of Nephrology

基　　金：基金项目：国家自然科学基金（81070578,81270809）;吉林大学科学前沿与交叉学科创新项目（200903056）

摘　　要：目的探讨血管紧张素Ⅱ（AngⅡ）1型受体拮抗剂（ARB）对2型糖尿病肾病（DN）大鼠肾小球内12．脂氧合酶（12-LO）活性及P钙黏蛋白（P．cadherin）表达的影响。方法用10^-7 mol／L Ang II处理足细胞24h。采用皮下包埋的微型渗透泵给雄性SD大鼠分别持续恒速注入12-LO代谢产物12羟二十烷四烯酸[12（S）-HETE，1mg·kg-1·d-1]和AngⅡ（400ng·kg-1·min-1）1周和2周。使用高脂饮食结合小剂量链脲菌素（STZ）诱导2型糖尿病模型，大鼠模型成功后随机分为2组：DN组和ARB（5mg·kg-1·d-1洛沙坦）组。以规律正常饮食大鼠作为对照组。6周后处死大鼠，收集尿、血液，提取肾脏，用系列过筛方法分离肾小球。采用ELISA、RT-PCR和Western印迹法分别检测相关指标。结果Ang II的直接刺激可以诱导足细胞及肾小球内12（s）．HETE含量增高（P〈0．01）。12（S）-HETE刺激使大鼠肾小球内AngII含量增高（P〈0．01）。与对照组比较，DN组血糖（P〈0．01）、肾质量／体质量（P〈0．01）和24h尿白蛋白明显增高（P〈0．01），但洛沙坦治疗后尿白蛋白（P〈0．05）、肾质量／体质量（P〈0．05）明显低于DN组。与对照组比较，DN组肾小球内12（s）．HETE含量明显增高（P〈0．01），P．cadherinmRNA和蛋白表达明显降低（P〈0．01），但洛沙坦治疗后肾小球内12（s）-HETE含量明显低于DN组（P〈0．05），P—cadherinmRNA和蛋白表达明显高于DN组（P〈0．05）。结论AngII通过激活12-LO诱导肾小球内P．cadherin的表达下调。ARB通过抑制12-LO活性而上调DN肾小球内P—cadherin表达，从而延缓DN的进展。Objective To investigate the effect of angiotensin II （Ang II） type 1 receptor blocker （ARB） on 12-1ipoxygenase （12-LO） activity and P-cadherin expression in type 2 diabetic rat glomeruli. Methods Podocytes were stimulated by 10^-7 mol/L Ang II for 24 hours. 12（S）-HETE （1 mg. kg-1. d-1） and Ang II （400 ng. kg-1. min -1） were infused to rats by osmotic mini-pump for 1 week and 2 weeks respectively. Rats fed with high fat diet received low dose streptozotocin （STZ） to make type 2 diabetes and divided into 2 groups： low dose STZ （DN group）, low dose STZ ＋ ARB treatment （Losartan group）. Rats fed with regular chow were used as control group. All the rats were sacrificed after 6 weeks. Urine, blood, kidney cortical tissue and isolated glomeruli by sieving method were collected at the end of study respectively. ELISA, RT-PCR and Western blotting for related target were performed respectively, Results Ang II increased 12（S）-HETE levels in podocytes and glomeruli （all P 〈 0.01）. Ang II levels in the glomeruli were significantly increased by 12（S）-HETE stimulation （P 〈 0.01）. Blood glucose, kidney/body weight and 24 hour urinary protein were increased in DN group compared with that in control group （all P 〈 0.01）. However, urine protein, Kidney/body weight were decreased in Losartan group compared with DN group （all P 〈 0.05）. Increment of 12（S）-HETE content and decrement of P-cadherin expression were observed in DN glomeruli compared with that in control group（all P 〈 0.01）. These abnormalities were prevented by administration of the losartan （all P 〈 0.05）. Conclusions Ang II can down-regulate glomerular P-cadherin expression via activation of 12-LO. ARB can ameliorate the progression of DN via up- regulation of glomerular P- eadherin through inhibition of 12-LO activation in type 2 DN rats.

关 键 词：血管紧张素Ⅱ 1型受体拮抗剂 糖尿病肾病 脂氧合酶 血管紧张素Ⅱ 钙黏着糖蛋白类 

分 类 号：R587.2[医药卫生—内分泌] R692.9[医药卫生—内科学]