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

足细胞线粒体功能及其在蛋白尿和肾小球硬化中的作用研究。

• 批准号: 18590879
• 负责人: YAMAGATA Kunihiro
• 金额: $ 2.34万
• 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: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590879/
• 关键词: Mitochondria; Mitocondirial DNA; slit-membrane proteins; glomerular epithelial cells; mitochondurial DNA depletion; ミトコンドリアDNA; マウスモデル; ネフリン; ポドシン

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.

在线粒体(Mt)DNA 4698bp缺失突变的有丝分裂小鼠中，由于mtDNA突变率的增加，死于肾功能衰竭并局灶性肾小球硬化(FGS)病变。本研究试图分析有丝分裂小鼠FGS损伤的发生机制。在有丝分裂小鼠中，检测到一只18周龄mtDNA突变超过70%的小鼠蛋白尿，在20周龄达到高峰，然后在22周龄死亡。在一只20周龄的小鼠身上也检测到了蛋白尿，突变率在50-69%之间，尽管它可以活到28周，而蛋白尿逐渐增加。对于突变率在10-49%之间的小鼠，在28周龄时轻微观察到蛋白尿。一只突变率超过70%的小鼠在20周龄后出现FGS病变，随后高速发展为全身性硬化症。当蛋白尿达到峰值时，肾小球内neparin和podocin的表达水平均升高。这两种蛋白的mRNA在蛋白尿高峰后均可观察到，但之后蛋白和mRNA的产量均下降。我们的研究表明，肾小球上皮细胞mtDNA异常积聚导致肾炎期裂隙膜蛋白和mRNA表达上调，但随着年龄的增长和mtDNA异常积聚的增多，肾小球上皮细胞与基底膜脱离，形成FGS损害。

项目成果

Mitochondrial dysfunction in foca1 segmental gIomeruloselersis of puromycin aminonucleoside nephrosis.

嘌呤霉素氨基核苷肾病局灶节段性肾小球硬化的线粒体功能障碍。

• 发表时间: 2006
• 期刊: Kidney Int. 69・7
• 作者: Hagiwara M;Yamagata K;Capaldi RA;Koyama A.
• 通讯作者: Koyama A.

Risk factors for chronic kidney disease in a community-based population: a 10-year follow-up study

• DOI: 10.1038/sj.ki.5002017
• 发表时间: 2007-01-01
• 期刊: KIDNEY INTERNATIONAL
• 影响因子: 19.6
• 作者: Yamagata, K.;Ishida, K.;Koyama, A.
• 通讯作者: Koyama, A.

Pathological roles of mitochondrial dysfunction in podocyte injry

线粒体功能障碍在足细胞损伤中的病理作用

• 发表时间: 2007
• 期刊: The Japanese Journal of Nephrology 49. 2
• 作者: Yamagata K;Hagiwara M
• 通讯作者: Hagiwara M

Tubulointerstitial nephritis and uveitis syndrome associated with hyperthyroidism.

与甲状腺功能亢进相关的肾小管间质性肾炎和葡萄膜炎综合征。

• 发表时间: 2006
• 期刊: Clin Exp Nephrol. 10・3
• 作者: Ebihara I;Hirayama K;Usui J;Seki M;Higuchi F;Oteki T;Kobayashi M;Yamagata K.
• 通讯作者: Yamagata K.

A novel apolipoprotein E mutation, ApoE Tsukuba (Arg 114 Cys), in lipoprotein glomerulopathy

• DOI: 10.1093/ndt/gfm735
• 发表时间: 2008-01-01
• 期刊: NEPHROLOGY DIALYSIS TRANSPLANTATION
• 影响因子: 6.1
• 作者: Hagiwara, Masahiro;Yamagata, Kunihiro;Saito, Takao
• 通讯作者: Saito, Takao