The sieving of plasma components occurs in the kidney through the glomerula
r capillary wall. This filter is composed of three layers; endothelium, glo
merular basement membrane (GBM), and podocyte foot processes connected by s
lit diaphragms. Defects in this barrier lead to proteinuria and nephrotic s
yndrome. Previously, defective GBM was regarded to be responsible for prote
inuria. However, recent work on genetic diseases has indicated that podocyt
es and the slit diaphragm are crucial in restricting protein leakage. Conge
nital nephrotic syndrome of the Finnish type (NPHS1) is caused by mutations
in a novel NPHS1 gene, which encodes for a cell adhesion protein, nephrin.
This protein is synthesized by podocytes, and seems to be a major componen
t of the slit diaphragm. In severe NPHS1, lack of nephrin leads to missing
slit diaphragm. The role of nephrin in acquired kidney diseases remains unk
nown. In addition to nephrin, other podocyte proteins (podocin, alpha -acti
nin-4, CD2AP, FAT) have recently been identified and associated with the de
velopment of proteinuria. It seems that the slit diaphragm and its interpla
y with the podocyte cytoskeleton is critical for the normal sieving process
, and defects in one of these components easily lead to proteinuria.