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

线粒体功能和线粒体 DNA 突变与局灶节段性肾小球硬化的关系

• 批准号: 15590841
• 负责人: YAMAGATA Kunihiro
• 金额: $ 2.11万
• 依托单位: University of Tsukuba
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590841/
• 关键词: Focal and segmental glomerular sclerosis; mitochondria; Mitochondrial DNA; mitochondrial protein; oxidative stress; podocyte; deletion mutation

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.

为了阐明线粒体DNA（mtDNA）在局灶节段性硬化症发病机制中的作用，我们通过多种分子和组织化学方法分析了mtDNA状态与Fawn Hooded高血压大鼠肾脏随年龄增长的病理变化的关系。所有大鼠的血压和蛋白尿均随着年龄的增长而逐渐升高。第4834章 肾组织中mtDNA的缺失在肾脏中也观察到逐渐增加。 mtDNA 4834 缺失突变的主要定位在足细胞中，这些变化在 20 周后变得明显。足细胞中的线粒体 DNA 与抗 8-OHdG 抗体发生反应，并且这种变化从 8 周起几乎保持不变。此外，20周后观察到肾小球中COX I的节段性缺失，肾小球内COX I表达显着降低，但COX IV表达没有变化。总之，足细胞的线粒体 DNA 遭受了严重的活性氧损伤。此外，还观察到线粒体DNA原位损伤和线粒体DNA编码的线粒体酶缺陷。这些结果表明肾小球上皮线粒体功能障碍可能是局灶节段性硬化病变的重要致病改变。

项目成果

Rapid analysis of mitochondrial DNA depletion by fluorescence in situ hybridization and immunocytochemistry: Potential strategies for HIV therapeutic monitoring

• DOI: 10.1369/jhc.3a6209.2004
• 发表时间: 2004-08-01
• 期刊: JOURNAL OF HISTOCHEMISTRY & CYTOCHEMISTRY
• 影响因子: 3.2
• 作者: Janes, MS;Hanson, BJ;Capaldi, RA
• 通讯作者: Capaldi, RA

巣状糸球体硬化症の病態生理

局灶性肾小球硬化的病理生理学

• 发表时间: 2004
• 期刊: Medical Practice 21(5)
• 作者: 山縣邦弘;萩原正大;小山哲夫
• 通讯作者: 小山哲夫

Apheresis for MPO-ANCA-associated RPGN ; Indications and Efficacy : Lessons Learned from Japan Nationwide Survey of RPGN

MPO-ANCA 相关 RPGN 的血浆分离术；

• 发表时间: 2005
• 期刊: J Clinical Apheresis 20(In press)
• 作者: Yamagata K;Koyama A et al.
• 通讯作者: Koyama A et al.

Glomerular crescents predominantly express cadherin-catenin complex in pauci-immune-type crescentic glomerulonephritis

• DOI: 10.1046/j.1365-2559.2003.01660.x
• 发表时间: 2003-08-01
• 期刊: HISTOPATHOLOGY
• 影响因子: 6.4
• 作者: Usui, J;Kanemoto, K;Nagata, M
• 通讯作者: Nagata, M

Rossignol R, Gilkerson R, Aggeler R, Yamagata K, Remington SJ, Capaldi RA.: "Energy substrate modulates mitochondrial structure and oxidative capacity in cancer cells"Cancer Research. 64(3). 985-993 (2004)

Rossignol R、Gilkerson R、Aggeler R、Yamagata K、Remington SJ、Capaldi RA.：“能量底物调节癌细胞中的线粒体结构和氧化能力”癌症研究。