慢性间歇性低氧对大鼠肾脏氧化应激损伤及HIF-1α表达的影响

Effect of chronic intermittent hypoxia on renal oxidative stress damage and HIF-1α expression in rats

目的:观察慢性间歇性低氧(CIH)大鼠肾组织形态学及其氧化应激相关指标变化,探讨CIH的肾损害机制。方法:将40只SD大鼠随机分为4组,CIH组2周和4周组(2IH和4IH)以及对照组2周和4周组(2C和4C),每组10只,采用化学比色法检测血清SOD活性,肾脏称重计算肾体比,HE染色、PAS染色和Masson染色法观察肾组织病理结构变化,real-time PCR法检测肾组织HIF-1α、Cu/Zn SOD和Mn SOD mRNA的表达变化。结果:(1)各组大鼠平均肾重、体重和肾体比差异无统计学意义(均P>0.05);IH组大鼠肾组织存在病理损害,HE和PAS染色示肾小球系膜和基底膜轻度增生,肾小管上皮水肿,4周组损害较明显;Masson染色IH和对照组均未见纤维化改变。(2)化学比色法示IH组血清SOD活性低于相应对照组(均P<0.05),4IH组下降更明显(P<0.05)。Cu/Zn SOD和Mn SOD mRNA组间比较差异有统计学意义(均P<0.05);Cu/Zn SOD mRNA表现为IH组低于相应对照组(均P<0.05),4IH组与2IH组比较差异无统计学意义;Mn SOD mRNA的表达4IH组较4C组下调,差异有统计学意义(P<0.05),4IH组明显高于2IH组(P<0.05),2IH和2C组比较差异无统计学意义(P>0.05)。IH组肾组织HIF-1α的mRNA表达均高于相应对照组(均P<0.05),4IH组高于2IH组(P<0.05)。结论:CIH可诱导大鼠肾小球、小管结构异常,但4周CIH尚未引起肾组织纤维化改变。CIH可通过上调HIF-1αmRNA和下调Cu/Zn SOD、Mn SOD mRNA的表达,参与氧化应激损伤过程。

AIM： To investigate the mechanism of renal damage in chronic intermittent hypoxia（ CIH） rat model. METHODS： The Sprague-Dawley rats were randomly divided into 2-week CIH group（ 2IH）,2-week simulated air control group（ 2C）,4-week CIH group（ 4IH） and 4-week simulated air control group（ 4C）. HE staining,PAS staining and Masson staining were used for histological evaluation. Blood was collected for the measurement of superoxide dismutase（ SOD）. The mRNA expression of hypoxia-inducible factor-1α（ HIF-1α）,manganese superoxide dismutase（ Mn SOD）,copper / zinc superoxide dismutase（ Cu / Zn SOD） was detected by real-time PCR. RESULTS：（ 1） No significance difference of renal weight,body weight,and the ratio of renal weight to body weight was observed,while IH caused morphologic kidney damage,especially in 4IH group. Hypertrophy of epithelial cells in the kidney tubles and dilation in the glomeruli were observed under light microscope with HE and PAS staining,especially in 4IH group. Masson staining showed no significant fibrotic response in the kidney of the rats exposed to IH.（ 2） The SOD levels in the serum and kidney were decreased after CIH. Compared with the corresponding control groups,the levels of serum SOD were significantly lower in CIH groups,especially in 4IH group. The mRNA expression of Cu / Zn SOD and Mn SOD in CIH groups decreased significantly as compared with control groups. The mRNA levels of HIF-1α were significantly higher in CIH groups than those in the corresponding control groups. CONCLUSION： CIH induces abnormalities of glomeruli and convoluted tubules,while 4-week IH exposure has not led to fibrotic response. CIH participates in the process of renal oxidative stress damage by upregulating HIF-1α transcription and downregulating Cu / Zn SOD and Mn SOD transcription.