肾小管上皮细胞线粒体氧化损伤在肾间质纤维化中的病理学机制研究

The pathogenic role of mitochondria oxidative damage in renal tubular epithelial cells on kidney interstitial fibrosis

目的:研究肾小管上皮细胞线粒体氧化损伤在肾间质纤维化中的病理学机制。方法:80只雄性大鼠随机平分为假手术组和UUO模型组,每组40只,行大鼠左侧输尿管结扎术,假手术组游离左侧输尿管但不予结扎,其余手术与UUO模型组相同。分别于术后d3、d7、d10、d14、d21每组处死8只,取大鼠左侧肾脏。1检测并比较假手术组和UUO模型组大鼠线粒体相关基因的表达水平;2检测两组大鼠肾脏组织COX和SOD含量变化;3检测两组大鼠肾脏组织RIF指数变化;4检测并比较肾体比、肾功能和肾组织Hyp含量动态变化。结果:与假手术组大鼠相比,1UUO模型组大鼠的线粒体相关基因的表达水平显著升高(P<0.05),包括线粒体mt DNA、再生基因(PGC1a、NRF1和Tfam)、断裂基因(Mfn1、Mfn2和Opa1)和融合基因(Drp1和Fis1);2UUO模型组大鼠在造模后10d、14d和21d,肾脏组织中的COX水平显著升高(P<0.05),SOD水平显著降低(P<0.05),造模时间越长,UUO模型组大鼠COX水平越高(P<0.05),SOD水平越低;3UUO模型组大鼠造模后10d、14d和21d,肾脏组织RIF指数均显著升高(P<0.05);4UUO模型组大鼠肾体比明显升高且一直维持在较高水平(P<0.05),造模时间越长,模型大鼠血清Scr和BUN水平及肾组织Hyp含量水平逐渐升高,与假手术组相比均具有显著差异(P<0.05)。结论:与假手术组大鼠相比,UUO模型组大鼠肾组织中的线粒体更活跃,线粒体基因、再生基因、断裂基因和融合基因含量升高,COX含量升高,SOD含量降低,RIF指数升高,肾体比、血清Scr和BUN和肾组织Hyp水平显著升高。

Objective：This study was undertaken to investigate the pathogenic role of mitochondria oxidative damage in renal tubular epithelial cells on kidney interstitial fibrosis.Methods：The 80 female rats, equally divided into sham-operated group and UUO group,were ligated of the left ureter. The sham-operated group freed the left ureter but were not ligated and other surgery was the same with the UUO group. 8 rats were sacrificed on 3d, 7d, 10 d, 14 d and 21 d in each group separately, and the left kidneys were removed by surgery. 1 Measure and compare the mitochondria associated genes between the sham-operated group and the UUO group; 2 test the level of COX and SOD in the two groups; 3 measure the RIF index of the kidney; 4 detect and compare the kidney/body weight, the function of kidney and the level of Hyp in kidney. Results：When compared to the sham-operated group, 1the UUO group had a higher level of mitochondria associated genes such as mt DNA, PGC1 a, NRF1, Tfam, Mfn1, Mfn2, Opa1, Drp1 and Fis1（P0.05）; 2on 10 d, 14 d and 21 d, the UUO group had a higher level of COX and a lower level of SOD in kidney, and the level of COX and SOD was time-dependent（P0.05）;3the UUO group had a higher RIF index on 10 d, 14 d, and 21d（P0.05）; 4the UUO group had a higher ratio of kidney/body weight, a higher serum level of Scr and BUN, a higher level of Hyp in kidney（P0.05）. Conclusions：When compared to the sham-operated group, the UUO group had a much more active mitochondria indicated by the higher level of mt DNA, regeneration genes, split genes and fused genes, a higher level of COX, a lower level of SOD, it also had a higher level of RIF index, kidney/body weight, a higher level of serum Scr and BUN, a higher level of Hyp in kidney.