The Glomerular Endothelium Restricts Albumin Filtration

Abstract

Inflammatory activation and/or dysfunction of the glomerular endothelium triggers proteinuria in many systemic and localized vascular disorders. Among them are the thrombotic microangiopathies, many forms of glomerulonephritis, and acute inflammatory episodes like sepsis and COVID-19 illness. Another example is the chronic endothelial dysfunction that develops in cardiovascular disease and in metabolic disorders like diabetes. While the glomerular endothelium is a porous sieve that filters prodigious amounts of water and small solutes, it also bars the bulk of albumin and large plasma proteins from passing into the glomerular filtrate. This endothelial barrier function is ascribed predominantly to the endothelial glycocalyx with its endothelial surface layer, that together form a relatively thick, mucinous coat composed of glycosaminoglycans, proteoglycans, glycolipids, sialomucins and other glycoproteins, as well as secreted and circulating proteins. The glycocalyx/endothelial surface layer not only covers the glomerular endothelium; it extends into the endothelial fenestrae. Some glycocalyx components span or are attached to the apical endothelial cell plasma membrane and form the formal glycocalyx. Other components, including small proteoglycans and circulating proteins like albumin and orosomucoid, form the endothelial surface layer and are bound to the glycocalyx due to weak intermolecular interactions. Indeed, bound plasma albumin is a major constituent of the endothelial surface layer and contributes to its barrier function. A role for glomerular endothelial cells in the barrier of the glomerular capillary wall to protein filtration has been demonstrated by many elegant studies. However, it can only be fully understood in the context of other components, including the glomerular basement membrane, the podocytes and reabsorption of proteins by tubule epithelial cells. Discovery of the precise mechanisms that lead to glycocalyx/endothelial surface layer disruption within glomerular capillaries will hopefully lead to pharmacological interventions that specifically target this important structure.

Keywords: endothelial dysfunction; endothelial surface layer; fenestrae; glycocalyx; hyaluronan; permselectivity; proteoglycans; thrombotic microangiopathy.

Figure 1

Components of the EC glycocalyx and ESL. (A) Structure of glycosaminoglycan chains. (B) Example of a branched, sialylated oligosaccharide side-chain. (C) Schematic representation of hyaluronan synthase (HAS)-mediated hyaluronan synthesis at the cell membrane. (D) Schematic representation of major EC glycocalyx components. (E) Schematic representation of major ESL components. (F) Artistic representation of the dense, bundled glycocalyx component. (G) Transmission EM image of a glomerular capillary wall with superimposed artistic representation of the glycocalyx (orange) and ESL (blue) thickness.