Role of nephrin in cell junction formation in human nephrogenesis

Nephrin is a cell adhesion protein located at the slit diaphragm area of gl omerular podocytes, Mutations in nephrin-coding gene (NPHS1)cause congenita l nephrotic syndrome (NPHS1). We studied the developmental expression of ne phrin, ZO-1 and. P-cadherin in normal fetal kidneys and in NPHS1 kidneys. W e used in situ hybridization and immunohistochemistry at light and electron microscopic levels. Nephrin and zonula occludens-1 (ZO-1) were first expre ssed in late S-shaped bodies. During capillary loop stage, nephrin and ZO-1 localized at the basal margin and in the cell-cell adhesion sites between developing podocytes, especially in junctions with ladder-like structures. In mature glomeruli, nephrin and ZO-1 concentrated at the slit diaphragm ar ea. P-cadherin was first detected in ureteric buds, tubules, and vesicle st age glomeruli, Later, P-cadherin was seen at the basal margin of developing podocytes, Fetal NPHS1 kidneys with Fin-major/Fin-major genotype did not e xpress nephrin, whereas the expression of ZO-1 and P-cadherin was comparabl e to that of control kidneys. Although early junctional complexes proved st ructurally normal, junctions with ladder-like structures and slit diaphragm s were completely missing. The results indicate that nephrin is dispensable for early development of podocyte junctional complexes. However, nephrin a ppears to be essential for formation of junctions with ladder-like structur es and slit diaphragms.