低氧诱导因子1α高表达对小鼠急性缺血性肾损伤的影响  

Hypoxia inducible factor 1α activation attenuates ischemia reperfusion injury of the kidney in mice

作　　者：张晓丽[1] 刘红[1] 邹建洲[1] 方艺[1] 蒋素华[1] 许迅辉[1] 丁小强[1] 

机构地区：[1]复旦大学附属中山医院肾内科,上海200032

出　　处：《中华肾脏病杂志》2007年第7期448-452,共5页Chinese Journal of Nephrology

基　　金：国家自然科学基金（30570860）;中国博士后基金（2005038126）;上海市科委重点基础课题（03jc14084）;上海市启明星人才培养追踪计划（04QMH1401）

摘　　要：目的探讨低氧预处理诱导低氧诱导因子1α（HIF-1α）高表达对小鼠肾缺血再灌注损伤（IRI）的影响及其可能机制。方法雄性C57BL／6N小鼠35只，随机分为健康对照组、氯化钴（CoCl2）组和8％O2组，每组10只；预处理12h后，以上3组各取5只，分为缺血再灌注（IR）组、CoCl2＋IR组、8％O2＋IR组；另设5只作为假手术对照组。采用夹闭双侧肾蒂30min的方法建立肾缺血动物模型，观察CoCl2和8％O2预处理对小鼠IR 24h后肾功能、肾组织病理和相关肾损伤指标的影响及与CoCl2和8％O2诱导HIF-1α及其保护性靶基因血红素氧化酶1（HO-1）表达之间的关系。结果CoCl2＋IR组小鼠的肾功能[BUN（35．2±12．2）mmol／L，Scr（34．0±9．7）μmol／L]和8％O2＋IR组小鼠的肾功能[BUN（31．8±9．1）mmol／L，Scr（41．6±10．6）μmol／L]均较IR组[BUN（65．8±2．6）mmol／L，Scr（229．5±11．2）μmol／L]显著改善（P〈0．01）；与此相一致，CoCl2＋IR组和8％O2＋IR组的病理学改变、细胞凋亡程度和波形蛋白的表达均明显低于IR组。另外，CoCl2组和8％O2组中HIF-1α及其靶基因HO-1的表达明显高于健康对照组。结论低氧预处理可上调体内HIF-1α表达，对小鼠IRI肾脏具有良好保护效果。Objective To explore the effects of pretreatment with cobalt chloride （CoCl2）or normbaric hypoxia（ 8%O2）on ischemia reperfusion injury （IRI）of the kidney in mice and its relationship to hypoxia inducible factor 1α （HIF-1α） and heme oxygenasel （HO-1）. Methods Thirty-five C57BL/6N male mice were randomly divided into 7 groups： control group, CoCl2 group, 8%O2 group, sham operation group, ischemia reperfusion （IR） group, CoCl2＋IR group and 8%O2＋IR group. IRI was induced in mice by clamping both renal pedicles for 30 min. The expression of HIF-1α and HO-1 were detected by Western blot. Renal function was reflected by blood urea nitrogen （BUN）and serum creatinine （Scr）. Morphologic changes were evaluated under light microscopy. Apoptosis in the kidney was detected by TUNEL staining. The expression of vimentin, a marker of tubulointerstitial damage, was detected by immunohistochemistry. Results Compared with sham group, elevation of BUN（65.8±2.6 vs 13.6±0.7, P〈0.01 ）,Scr（229.5±11.2 vs 6.5±0.8, P〈0.01 ） and morphological injury after the ischemic insult were found in IR group. Pretreatment with CoCl2 and 8%O2 induced significant functional improvement （CoCl2 treatment： BUN 35.2±12.2 vs 65.8±2.6, Scr 34±9.7 vs 229.5±11.2; 8%02 treatment：BUN 31.8±9.1 vs 65.8±2.6, Scr 41.6±10.6 vs 229.5±11.2 respectively, P〈0.01）associated with amelioration of tubulointerstital damage. In the kidneys of mice treated with CoCl2 and 8% O2,protein levels of HIF-1α and HO-1 were up-regulated significantly. Conclusion Pretreatment with CoCl2 or 8% O2 attenuates IRI of the kidney in mice mediated by activation of HIF-1α and expression of HO-1.

关 键 词：再灌注损伤 氯化钴 低氧诱导因子1 急性肾损伤 血红素氧化酶 

分 类 号：R686[医药卫生—骨科学]