Molecular Basis of Proteinuria

The glomerular filtration barrier is composed of endothelial cells, basement membrane, and podocytes. In recent years, remarkable progress has been made in our understanding of the molecular structure of the filtration barrier and its relation to the effectiveness of the barrier function. The glomerular basement membrane is composed of a multitude of proteins, including collagen IV, heparan sulfate proteoglycans, and laminin, among others. The slit diaphragm, which is seen as a membrane covering the space between adjacent foot processes close to the basement membrane, is an extremely important structure with a crucial role in permselectivity of the filtration barrier. Its composition is now understood to consist primarily of a unique protein called nephrin. Mutations in the gene-encoding nephrin are known to result in the Finnish type of nephrotic syndrome. The exact mechanism by which nephrin controls permselectivity is not yet clear, but it is known to interact with several podocyte proteins including CD2AP, podocin, and alpha-actinin-4. Abnormalities of any of these proteins may result in proteinuria. The role of nephrin and its associated proteins in the pathogenesis of common acquired glomerulopathies in humans is still under investigation. Normal function of podocyte also depends upon maintaining a fully mature and terminally differentiated phenotype. A host of transcription factors, especially WT1 and PAX2, play a significant role in modulating podocyte function.