Chapter 1 10 Glycocalyx and fenestrated endothelial cell The first layer of the glomerular filtration barrier is the glycocalyx. As the name implies, it consists mostly of various ‘sugary’ chains, which consist of negatively charged heparan sulphate glycosaminoglycan chains attached to heparan sulphate core proteins and hyaluronan. The glycocalyx has a role in mitigating inflammation, and coagulation.(4) The glycocalyx lines the specialized endothelial cells of the glomerulus. These endothelial cells have the distinguishing feature of being fenestrated with 60 nm pores. The negatively charged glycocalyx covering these pores is considered to be the first barrier between the vascular lumen and the ultrafiltrate that serum proteins such as albumin encounter. In end-stage renal disease, damage to the structural integrity and composition of the glycocalyx is observed.(5) Also, in experimental models where damage to the glycocalyx is induced, proteinuria occurs. As such, it is thought to be a vital part of the glomerular filtration barrier in the protection against proteinuria. Glomerular basement membrane The next layer is the glomerular basement membrane (GBM). It is an extracellular matrix that is proximally deposited by the glomerular endothelial cells and the visceral epithelial cell on the distal end. On electron microscopy, three GBM layers can be distinguished. These are the lamina rara interna on the vascular side, the lamina densa, and the lamina rara externa adjacent to the epithelial side. The GBM mainly contains laminin, collagen type IV, and heparan sulphate proteoglycans. It normally has a thickness between 300 and 400 nm. The GBM has an overall negative charge due to the sulphated glycosaminoglycan chains of the heparan sulphate proteoglycan aggregates. Heparan sulphate glycosaminoglycans Glomerular filtration occurs with both size and charge selectivity (6). Maintaining this selectivity and GFB integrity has long been attributed to heparan sulphate glycosaminoglycans (7, 8). As stated above, they are localized in both the glycocalyx and GBM. Heparan sulphate glycosaminoglycan chains consist of repeating disaccharide motifs that contain a uronic acid and a glucosamine derivative. Theoretically, up to 48 different motifs can be formed. Heparan sulphate synthesis starts with chain initiation, where a tetrasaccharide linkage region is formed and is covalently bound to a core protein. The next phase of HS synthesis consists of chain polymerization, which is dependent on enzymes encoded by the EXT1 and EXT2 genes. These enzymes form a co-polymerase that adds repeating disaccharide units consisting of D-glucuronic acid (GlcAβ4) and N-acetylglucosamine (GlcNAcα4). During chain polymerization, the polymer is also modified
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