Molecular Pathogenesis of Hereditary Glomerulosclerosis.

肾病综合征的特征是大量蛋白尿，是由连接相邻足细胞足突的裂隙膜功能或/和结构破坏引起的，是肾小球滤过屏障。人类分子遗传学的最新进展揭示了肾病综合征的发病机制，并表明在裂隙隔中表达的neaffin(NPHS1)和podocin(NPHS2)缺陷是导致早期肾病综合征的原因。为了了解podocin在发病机制中的作用，我们利用大鼠PAN诱导的肾病模型和稳定表达podocin的转基因细胞(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，Podocin从裂隙横隔膜向新形成的细胞连接募集。与这一发现一致，我们观察到Podocin在稳定转基因细胞的细胞-细胞连接中积累。Podocin存在于细胞-细胞连接，包括正常的裂隙膜以及PAN诱导的紧密连接，这表明podocin的作用是提供一个支架，允许高效积累分子，这是形成稳定的细胞连接所必需的。

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.