Genetic kidney diseases disclose the pathogenesis of proteinuria.
The sieving of plasma components occurs in the kidney through the glomerular capillary wall. This filter is composed of three layers: endothelium, glomerular basement membrane (GBM), and podocyte foot processes connected by slit diaphragms. Defects in this barrier lead to proteinuria and nephrotic syndrome. Previously, defective GBM was regarded to be responsible for proteinuria. However, recent work on genetic diseases has indicated that podocytes and the slit diaphragm are crucial in restricting protein leakage. Congenital 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 component of the slit diaphragm. In severe NPHS1, lack of nephrin leads to missing slit diaphragm. The role of nephrin in acquired kidney diseases remains unknown. In addition to nephrin, other podocyte proteins (podocin, alpha-actinin-4, CD2AP, FAT) have recently been identified and associated with the development of proteinuria. It seems that the slit diaphragm and its interplay with the podocyte cytoskeleton is critical for the normal sieving process, and defects in one of these components easily lead to proteinuria.
Jalanko
H
H
Hospital for Children and Adolescents and Biomedicum Helsinki, University of Helsinki, Finland. hannu.jalanko@hus.fi
Patrakka
J
J
Tryggvason
K
K
Holmberg
C
C
D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics; D006801:Humans; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology*; D008565:Membrane Proteins / Q000378:metabolism; D009154:Mutation; D009404:Nephrotic Syndrome / Q000150:complications / Q000151:congenital / Q000235:genetics*; D010750:Phosphoproteins / Q000378:metabolism; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D011507:Proteinuria / Q000235:genetics*
D008565:Membrane Proteins; D010750:Phosphoproteins; D011506:Proteins; C113267:nephrin