Molecular Pathogenesis of Hereditary Glomerulosclerosis.

遗传性肾小球硬化症的分子发病机制。

• 批准号: 14571026
• 负责人: TSUKAGUCHI Hiroyasu
• 金额: $ 2.24万
• 依托单位: The University of Tokushima
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14571026/
• 关键词: kidney; gene; nephrotic syndrome; renal failure; podocyte; ポドドサイト; ゲノム; 遺伝子変異; ネフローゼ症候群; 腎糸球体上皮

Nephrotic syndrome is characterized by a massive proteinuria and is caused by functional or/and structural disruption of slit membrane, which connects adjacent podocyte foot processes and serves as a glomerular filtration barrier. Recent advance in human molecular genetics shed light on the mechanism underlying nephrotic syndrome and showed that defects in nephrin (NPHS1) and podocin (NPHS2), both of which are expressed in the slit diaphragm, are responsible for early onset nephrotic syndrome.To understand the role of podocin in the pathogenesis, we analyzed podocin localization by using rat PAN-induced nephrotic model and transfected cells stably expressing podocin (mouse L cell and MDCK). In podocytes of PAN treated rats, podocin was recruited from the slit diaphragm to the newly formed cell junctions. Consistent with this finding, we observed accumulation of podocin into cell-cell junctions of stably transfected cells. The presence of podocin at cell-cell junctions, including normal slit membrane as well as PAN-induced tight junction, suggested that the role of podocin is to provide a scaffold that allows efficient accumulation of molecules, which is necessary to form stable cellular junctions.

肾病综合征以大量蛋白尿为特征，由连接相邻足细胞足突并作为肾小球滤过屏障的裂隙膜的功能或/和结构破坏引起。人类分子遗传学的最新进展揭示了肾病综合征的机制，并表明在狭缝隔膜中表达的nephrin （NPHS1）和podocin （NPHS2）的缺陷与早发性肾病综合征有关。为了了解podocin在肾病发病机制中的作用，我们利用pan诱导的大鼠肾病模型和稳定表达podocin的转染细胞（小鼠L细胞和MDCK）分析了podocin的定位。在PAN处理的大鼠足细胞中，足素从膈缝向新形成的细胞连接处募集。与这一发现一致，我们观察到podocin在稳定转染细胞的细胞-细胞连接处积累。podocin存在于细胞-细胞连接处，包括正常的狭缝膜和pan诱导的紧密连接处，这表明podocin的作用是提供一个支架，允许分子的有效积累，这是形成稳定的细胞连接所必需的。

项目成果

Maruyama K.: "NPHS2 mutation in sporadic steroid-resistance nephritic syndrome in Japanese children"Pediatric Nephrology. (In press).

Maruyama K.：“日本儿童散发性类固醇抵抗性肾病综合征中的 NPHS2 突变”小儿肾脏病学。

塚口裕康: "遺伝性ポドサイト腎症-症候性疾患"腎と透析. 55・5. 753-764 (2003)

Hiroyasu Tsukaguchi：“遗传性足细胞肾病 - 症状性疾病”《肾脏与透析》55・5（2003）。

塚口 裕康: "広範な家族歴を認めたIgA腎症の一症例"日本腎臓学会誌. 44(6). 526 (2002)

Hiroyasu Tsukaguchi：“具有广泛家族史的 IgA 肾病病例”，日本肾病学会杂志 44(6) 526 (2002)。

塚口裕康: "遺伝子異常からみた腎疾患巣状糸球体硬化症家系の遺伝子解析"内科. 92・1. 12-17 (2003)

Hiroyasu Tsukaguchi：“从遗传异常的角度对肾病局灶性肾小球硬化症家族进行遗传分析”《内科》92・1（2003）。

Tsukaguchi H: "NPHS2 mutations in late onset focal segmental glomerulosclerosis : R229Q is a common disease associated allele."J Clin Invest. 110. 1659-1666 (2002)

Tsukaguchi H：“迟发性局灶性节段性肾小球硬化症中的 NPHS2 突变：R229Q 是一种常见的疾病相关等位基因。”J Clin Invest。