氧化应激在尿酸致早期慢性肾脏病血管内皮损伤中的作用

Effect of Oxidative Stress on Endothelial Dysfunction in Early CKD with Hyperuricemia

目的:探讨氧化应激在尿酸所致早期慢性肾脏病(CKD)血管内皮损伤中的作用。方法:将雄性SD大鼠随机分为假手术组(A)、单侧肾切除组(B)和实验组(C)。通过右肾切除并喂养10周的方法建立早期CKD动物模型,实验组以尿酸酶抑制剂氧嗪酸钾灌胃稳步升高大鼠血尿酸。检测各组血清指标尿酸(UA)、肌酐(Scr)、一氧化氮(NO)、内皮素-1(ET-1)、丙二醛(MDA)、超氧化物歧化酶(SOD)等,光镜下观察血管壁病变以及Ⅰ型胶原在血管壁沉积等情况,分析C组与其他两组间氧化应激水平的差异。结果:各组大鼠肾病理均未见明显病变,且Scr差异无统计学意义,但C组UA水平明显升高(P<0.01)。A组血管壁未见明显病变,管壁见少量Ⅰ型胶原;C组可见内皮细胞脱落,内皮间隙增宽,细胞水肿,管壁炎症细胞聚集,血管中层平滑肌细胞增生,结构紊乱,血管壁见较多Ⅰ型胶原沉积;B组病变与C组相似,但程度较轻。C组血管壁Ⅰ型胶原阳性面积百分比显著升高(P<0.01)。C组NO明显低下(P<0.01),ET-1明显增高(P<0.05),NO/ET-1比值明显降低(P<0.01)。C组SOD显著降低(P<0.01),MDA显著升高(P<0.05)。单因素相关分析显示:UA与ET-1(r=0.9374,P<0.01)、Ⅰ型胶原阳性面积百分比(r=0.8403,P<0.01)呈显著正相关,与NO(r=-0.9462,P<0.01)、NO/ET-1比值(r=-0.9230,P<0.01)呈显著负相关;UA与MDA(r=0.8195,P<0.01)呈显著正相关,与SOD(r=-0.6885,P<0.05)呈显著负相关;NO与SOD(r=0.8179,P<0.01)呈显著正相关,与MDA(r=-0.9171,P<0.01)呈显著负相关;ET-1与SOD(r=-0.7793,P<0.01)呈显著负相关,与MDA(r=0.8658,P<0.01)呈显著正相关;NO/ET-1比值与SOD(r=0.8143,P<0.01)呈显著正相关,与MDA(r=-0.9143,P<0.01)呈显著负相关。结论:氧化应激是尿酸致早期CKD血管内皮细胞损伤的一个重要机制。

Objective：To discuss the relationship between oxidative stress and endothelial dysfunction in early CKD with hyperuricemia.Methods：The animal model was established by right-sided nephrectomy and fed with potassium oxonate,an inhibitor of uric acid enzyme for 10 weeks. Indices were measured,including serum creatinine （Scr）,serum uric acid （UA）,serum nitric oxide （NO）,serum endothelin-1（ET-1）,serum malonaldehyde （MDA）,serum super oxide dismutase（SOD）,the pathology of kidney and artery and collagenⅠof artery in the experimental group.Then these indices were compared with those in other two groups.Results：There was no obvious pathological change in the kidney of the three group.Compared with the right-sided nephrectomy group and the sham-operation group,the experimental one had significant higher level of UA,but there was no obvious difference in Scr among the three groups.There was no obvious pathological change in the artery of the sham-operation group.However,in the experimental one,the endothelial cells partly dropped from the artery,and the gap between them broadened.The smooth muscle cells proliferated in the experimental group,and there was obvious more collagen Ⅰ deposited in the artery.The pathological change of the right-sided nephrectomy group was similar to that of the experimental group,but at a more minor level.The experimental group had higher level of the percentage of collagen Ⅰpositive area（P〈0.01）,higher level of serum endothelin-1（P〈0.05） and higher level of serum malonaldehyde（P〈0.05） but lower level of serum nitric oxide（P〈0.01）,lower level of NO/ET-1 ratio（P〈0.01） and lower level of serum super oxide dismutase（P〈0.01）.Linear regression analysis showed that the level of serum uric acid had significant positive correlations with serum ET-1（r=0.937 4,P〈0.01） and the percentage of collagen Ⅰpositive area （r=0.840 3,P〈0.01）,but negative correlations with serum NO （r=-0.946 2,P0.01）and NO/ET-1 ratio （r=-0.923 0,P,0.01）.The level of serum uric acid had significant positive correlations with serum MDA （r=0.819 5,P〈0.01）,but negative correlation with serum SOD（r=-0.688 5,P0.05）.The level of serum NO had significant positive correlation with serum SOD（r=0.817 9,P〈0.01）,but negative correlations with serum MDA（r=-0.917 1,P〈0.01）.The level of serum ET-1 had significant positive correlations with serum MDA（r=0.865 8,P0.01）,but negative correlation with serum SOD（r=-0.779 3,P〈0.01）.NO/ET-1 ratio had significant positive correlation with serum SOD（r=0.814 3,P〈0.01）,but negative correlations with serum MDA（r=-0.914 3,P〈0.01）.Conclusion：There was significant endothelial dysfunction in early CKD with hyperuricemia,and oxidative stress may be an important mechanism.