中文摘要：

目的观察慢性间断缺氧（chronic intermittent hypoxia，CIH）导致。肾脏损伤的可能机制及金属硫蛋白（metallothionein，MT）是否对其具有保护作用。方法8～10周龄的雄性MT-1过表达（MT．TG）小鼠及其野生型（wT）小鼠各12只，随机数字法分为模拟对照组（n=6）及CIH组（n=6），进行8周缺氧-再氧合模型实验。CIH处理方案为20．9％0：与8％0：吸入氧浓度分数（F．O：）交替进行，30次/h，12h/d，最低氧饱和度变化维持在60％-70％。实验终点采用硫代巴比妥酸比色法测定肾脏组织脂质过氧化产物丙二醛（malondialdehyde，MDA）含量，并用组织病理学及Western印迹方法检测肾脏损伤及信号通路蛋白的表达情况。结果与模拟对照组比较，wTCIH组肾脏组织纤维化程度及促纤维生长因子结缔组织生长因子（CTGF）、1型纤溶酶原激活物抑制物（PAI-1）蛋白表达显著增加（P〈0．01），而MT-TGCIH组无明显变化。与模拟对照组比较，WTCIH组肾脏组织脂质过氧化产物MDA（也是细胞氧化损伤的指标）显著增加（P〈0．01），而MT．TGCIH组无明显变化。与模拟对照组比较，wTCIH组。肾脏组织缺氧诱导因子1α（HIF-1α）、转化生长因子131（TGF-β1）蛋白表达及Smad2磷酸化水平显著增加（P〈0．01），而MT-TGCIH组无明显变化。与模拟对照组比较，wTCIH组肾脏组织抗氧化物质MT蛋白表达显著减少（P〈0．01），而MT．TGCIH组无明显变化。结论CIH导致肾脏损伤与氧化应激及氧化损伤有关。CIH可能通过上调肾脏组织的HIF-1α表达，启动TGF-β1-Smad2信号传导通路，最终导致肾脏组织纤维化。抗氧化物质MT对CIH导致的肾脏损伤有保护作用，其可能的机制是MT的抗氧化作用抑制了CIH引起的肾脏组织HIF-1α表达上调，从而抑制了TGF-β1-Smad2信号传导通路。

英文摘要：

Objective To investigate the mechanism of chronic intermittent hypoxia （CIH） induced renal injury and the protection of metallothionein （MT）. Methods 8-10 weeks old male MT-1 transgenic （MT-TG） mice （n=12） and the wide type （WT） mice （n=12） were randomly divided into two groups respectively, Air mimic control（Ctrl） group （n=6） and CIH group （n=6）. The period of chronic intermittent hypoxia was continued for 8 weeks. The CIH paradigm consisted of 20.9% 02 and 8% 02 fraction of inspiration 02 （FiO2） alternation cycles （30 episodes per hour） with 20 seconds at the nadirFiO2 for 12 hours/day during daylight. The nadir hemoglobin oxygen saturations mainly ranged from 60% to 70%. Urine, blood, kidney were collected at the end of study respectively. Histopathology, Western blotting and colorimetric method for related target were performed respectively. Results In WT mice, renal fibrosis, the expression of connective tissue growth factor （CTGF）, type- 1 plasminogen activator inhibitor （PAl- 1）, hypoxia inducible factor lα （HIF-1α）, transforming growth factor β1 （TGF-β1）, phosphorylated Smad2 and the MDA content were significantly increased by CIH （P 〈 0.01）. In WT mice, the expression of MT detected by using Western blotting was significantly decreased by CIH （P 〈 0.01）. However, in MT-TG mice, above-mentioned indicators showed no significant difference between CIH and Ctrl group. Conclusions Oxidative stresses is the main mechanism of CIH- induced renal injury. The possible molecular mechanism of CIH induced renal injury is that CIH increases the expression of HIF- lα in kidney tissue, then activate the TGF- β1- Smad2 signaling pathway and lead to the renal fibrosis. The protection of MT on CIH-induced renal injury may be via its antioxidant effect.