厄贝沙坦对单侧输尿管梗阻大鼠肾组织缺氧诱导因子1α和结缔组织生长因子表达的影响

Effects of irbesartan on the expression of hypoxia- induced factor lot and connective tissue growth factor in the kidney of unilateral ureteral ligation operation model rats

目的观察缺氧诱导因子1α（HIF-1α）及结缔组织生长因子（CTGF）在慢性肾小管间质纤维化中的表达，以及血管紧张素Ⅱ受体拮抗剂（ARB）厄贝沙坦对其影响。方法应用单侧输尿管结扎手术建立单侧输尿管梗阻（UUO）模型。将健康成年的雄性SD大鼠按随机数字表法分为3组：假手术组（n=10）、模型组（n=10）和厄贝沙坦组（n=10）。后者术前2d开始给厄贝沙坦，假手术组和模型组仅予等量生理盐水灌胃。观察各组大鼠第2周肾功能、24h尿蛋白量和肾组织病理学改变。原位杂交和Western印迹法检测HIF-1α、CTGF在肾小管间质中的表达。结果与假手术组比较，模型组BUN、Scr及24h尿蛋白量增高（均P〈0．05）。肾组织HIF-1α mRNA及蛋白表达亦显著增高（均P〈0．05），主要分布在小管间质细胞的胞质；HIF-1α mRNA的表达与CTGF mRNA的表达呈正相关（r=0．697，P〈0．01）。与模型组比较，厄贝沙坦组大鼠尿蛋白量减少[（103．44±8．76）mg／24h比（278．23±26．15）mg／24h，P〈0．01]，Scr下降[（109．15±3．93）μmol／L比（185．04±13．45）μmol／L，P〈0．01]，肾小管间质病变面积减少（0．28±0．02比0．51±0．05，P〈0．01），肾小管间质细胞的HIF-1α mRNA和蛋白、CTGFmRNA和蛋白表达均显著减少（均P〈0．01）。结论单侧输尿管梗阻大鼠肾间质HIF-1α和CTGF表达明显增高，厄贝沙坦可能通过下调HIF-1α和CTGF的表达来改善肾脏纤维化。

Objective To investigate the expression of hypoxia-induced factor 1α （HIF- 1α） and connective tissue growth factor （CTGF） in the kidneys of unilateral ureteral ligation operation （UUO） model rats and the effect of irbesartan on the expression. Methods Thirty healthy adult male SD rats were randomly divided into 3 groups： sham operation group （n = 10）, UUO group （n = 10） and irbesartan group （n = 10, UUO rats treated with irbesartan by lavage 2 days before operation）. The rats in sham group and UUO group were treated with equal normal saline by lavage. Renal function, histopathological changes, urinary protein of 24 hours in rats at week 2 were measured. In situ hybridization and Western blotting were applied to measure the expression of HIF- 1α and CTGF.Results At week 2, the levels of BUN, Scr and the expressions of HIF- 1α and CTGF were significantly increased in UUO group compared with those in sham group （all P〈 0.01）. There was significant positive correlation between HIF-1α mRNA and CTGF mRNA （r = 0.697, P 〈 0.01）. Compared with UUO group, the levels of urine protein and Scr were significantly decreased [（103.44±8.76） mg/24 h vs （278.23±26.15） mg/24 h, P 〈 0.01; （109.15±3.93） μmol/L vs （185.04±13.45） μmol/L P 〈 0.01], and renal tubulointerstitial lesion area became smaller （0.28±0.02 vs 0.51 ±0.05, P 〈 0.01） in irbesartan group. The expression of HIF-1α mRNA and protein was also significantly decreased after the treatment of irbesartan （all P 〈 0.01）. Conclusions The expressions of HIF-1α and CTGF in UUO rats increase significantly. Irbesartan can improve renal fibrosis through down-regulating the expression of HIF-1α and CTGF.