Molecular Pathogenesis of Hereditary Glomerulosclerosis.

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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.