General introduction and outline 11 1 by various sulfotransferases and an epimerase leading to GlcNAc N-deacetylation/Nsulfation, epimerization of GlcA to L-iduronic acid (IdoA), and 2, 3, and 6-O-sulfation. These modifications not only result in an overall negative charge, but also the formation of ligand binding sites, such as FGF-2, antithrombin, chemokines, and cytokines. Thus, when chain polymerization is impaired due to a lack of EXT1 or EXT2, no modification can take place and hence the heparan sulphate is functionally impaired.(9) Podocyte and slit diaphragm Lastly, the distal end of the GFB is covered by visceral epithelial cells or podocytes. Podocytes gained their name from the Greek words podos (ποδος), which means foot, and kutos (κύτος), meaning jar or vessel, and used as a term to describe cells. One of the characteristics of podocytes is the presence of interdigitating foot processes called pedicles. The remaining space between these processes creates so-called filtration pores or slit diaphragms. The diaphragm is not an open connection to Bowman’s space. Adjacent foot processes are connected by nephrin (NPHS1) and NEPH1 (KIRREL1).(10) These proteins connect adjacent foot processes by spanning the slit diaphragm and attaching to the actin cytoskeleton of podocytes. The actin cytoskeleton and dynamin When podocytes are damaged, loss of architectural organization of the cytoskeleton occurs, which leads to retraction and effacement of the podocyte and its foot processes. The pathways and proteins responsible for podocyte cytoskeletal organization are steadily being uncovered. One of these proteins is dynamin, a small GTPase that is primarily known for its role clathrin-coated vesicle budding in neurons. It has now been described to be involved in the turnover of nephrin, regulation of actin, and endocytosis of albumin by podocytes, making it a potential future therapeutical target for preventing proteinuria. (11-14) Tubular reabsorption mechanisms After passing the glomerular filtration barrier, the ultrafiltrate enters Bowman’s space. Afterwards, the ultrafiltrate passes various parts of the tubule, where its content is altered through re-absorption and secretion which occur in both active and passive manners. Normally, when serum proteins such as albumin are indeed able to pass the glomerular filtration barrier, they are re-absorbed by proximal tubular epithelial cells. Tubular reabsorption mechanisms are not only responsible for the re-absorption of filtered protein, but also that of for example urea, bicarbonate, phosphate, glucose, and
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