Involvement of mitochondrial function and mitochondrial DNA mutations in focal segmental glomerulosclresosis

为了阐明线粒体DNA（mtDNA）参与局灶性节段性硬化病变的发病机制，我们分析了线粒体DNA状态的几种分子和组织化学方法与病理变化发生在年龄的Fawn Hooded高血压大鼠的肾脏。随着年龄的增长，所有大鼠的血压和蛋白尿逐渐升高。此外，如观察到的，肾组织中mtDNA的4834缺失在肾中逐渐增加。线粒体DNA 4834缺失突变主要定位于足细胞，20周后变化明显。足细胞中的线粒体DNA与抗8-OHdG抗体反应，从8周开始，这种变化几乎不变。此外，20周后观察到肾小球中考克斯I节段性缺失，肾小球内考克斯I表达显著减少，但考克斯IV表达无变化。提示足细胞线粒体DNA受到了严重的活性氧损伤。此外，还观察到原位mtDNA损伤和mtDNA编码的线粒体酶缺陷。提示肾小球上皮细胞线粒体功能障碍可能是局灶节段性硬化的重要病理改变。

In order to clarify the involvement of mitochondrial DNA(mtDNA) in the pathogenesis of focal segmental sclerosis lesions, we analyzed mtDNA status by several molecular and histochemical approaches in relation to pathological changes occurring with age in the kidney of the Fawn Hooded hypertensive rat. Blood pressure and proteinuria were gradually elevated with aging in all rats. Also the 4834 deletion of mtDNA in kidney tissue gradually increased in the kidneys as observed. The main localization of the mtDNA 4834 deletion mutation was seen to be in podocytes and these changes became obvious after 20 weeks. MtDNA in podocytes was shown to react with an anti 8-OHdG antibody, and this change was almost constant from 8 weeks on. Further, the segmental absence of COX I in glomeruli was observed after 20 weeks, Intra-glomerular COX I expression was significantly reduced, however, COX IV expression was not changed. In conclusion, it is suggested that the mtDNA of podocytes suffers critical reactive oxygen damage. Furthermore, in situ mtDNA damage, and mtDNA-encoded mitochondrial enzyme deficiency were also observed. These results suggest that glomerular epithelial mitochondrial dysfunction might be an important pathogenic change in focal segmental sclerosis lesions.