Studies on mitochondrial function of podocyte, and its role for proteinuria and glomerular sclerosis.

线粒体DNA（mtDNA）4698 bp缺失突变的线粒体小鼠，由于mtDNA突变率的增加，死于肾功能衰竭并发局灶性肾小球硬化（FGS）病变。本研究以线粒体DNA突变率超过70%的小鼠为研究对象，在18周龄时检测到蛋白尿，20周龄时蛋白尿达到高峰，22周龄时死亡。在20周龄的小鼠中也检测到蛋白尿，突变率在50-69%之间，尽管它可以活到28周龄，而蛋白尿逐渐增加。在突变率在10- 49%之间的小鼠的情况下，在28周龄时观察到轻微的蛋白尿。突变率超过70%的一只小鼠在20周龄后出现FGS病变，随后以高比率发展为全脑硬化。肾小球内nephrin和podocin的表达水平在蛋白尿达到峰值时均升高。在蛋白尿高峰期后，两种蛋白质的mRNA都有表达，但随后蛋白质的表达和mRNA的表达均下降。我们的研究表明，肾小球上皮细胞中异常mtDNA的积累导致了肾炎期裂膜蛋白和mRNA的上调，然而，随着年龄的增长，异常线粒体DNA的积累增多，导致肾小球上皮从GBM上脱落，形成FGS病变。

In a mito-mouse, which has 4698bp deletion mutation of mitochondrial (mt) DNA, dies from renal failure complicating with focal glomerular sclerosis (FGS) lesion, responding to increasing amount of mutation rate of mtDNA. We try to analyze mechanisms for developing FGS lesion in mito-mouse in this study.In mito-mouse, proteinuria was detected in a mouse with the mutatied mtDNA exceeding 70% at the age of 18 weeks, which came to the peak at the age of 20weeks, then finally died at the age of 22weeks. Proteinuria was also detected in a mouse with the mutation rate between 50-69% at the age of 20weeks, although it could live until 28weeks while proteinuria gradually had increased. In the case of a mouse with the mutation rate between 10-49%, proteinuria was slightly observed at the age of 28weeks. A mouse with the mutation rate exceeding 70% revealed FGS lesions after the age of 20weeks, which developed global sclerosis at high rate afterwards. The expression levels of both intraglomerular nephrin and podocin increased when proteinuria level came to the peak point. The mRNA of both proteins was observed after the peak of proteinuria, nevertheless, the production of proteins, as well as that of mRNA, both dropped down afterwards.From our study, accumulation of abnormal mtDNA in glomerular epithelium results in up-regulation of slit membrane protein and mRNA during nephritic phase, however, with ageing and more accumulated abnormal mtDNA results in detachment of glomerular epithelium from GBM and forms FGS lesion.