Endothelial glycocalyx dysfunction in disease: albuminuria and increased microvascular permeability

Abstract

Appreciation of the glomerular microcirculation as a specialized microcirculatory bed, rather than as an entirely separate entity, affords important insights into both glomerular and systemic microvascular pathophysiology. In this review we compare regulation of permeability in systemic and glomerular microcirculations, focusing particularly on the role of the endothelial glycocalyx, and consider the implications for disease processes. The luminal surface of vascular endothelium throughout the body is covered with endothelial glycocalyx, comprising surface-anchored proteoglycans, supplemented with adsorbed soluble proteoglycans, glycosaminoglycans and plasma constituents. In both continuous and fenestrated microvessels, this endothelial glycocalyx provides resistance to the transcapillary escape of water and macromolecules, acting as an integral component of the multilayered barrier provided by the walls of these microvessels (ie acting in concert with clefts or fenestrae across endothelial cell layers, basement membranes and pericytes). Dysfunction of any of these capillary wall components, including the endothelial glycocalyx, can disrupt normal microvascular permeability. Because of its ubiquitous nature, damage to the endothelial glycocalyx alters the permeability of multiple capillary beds: in the glomerulus this is clinically apparent as albuminuria. Generalized damage to the endothelial glycocalyx can therefore manifest as both albuminuria and increased systemic microvascular permeability. This triad of altered endothelial glycocalyx, albuminuria and increased systemic microvascular permeability occurs in a number of important diseases, such as diabetes, with accumulating evidence for a similar phenomenon in ischaemia-reperfusion injury and infectious disease. The detection of albuminuria therefore has implications for the function of the microcirculation as a whole. The importance of the endothelial glycocalyx for other aspects of vascular function/dysfunction, such as mechanotransduction, leukocyte-endothelial interactions and the development of atherosclerosis, indicate that alterations in the endothelial glycocalyx may also be playing a role in the dysfunction of other organs observed in these disease states.

Hyaluronidase 1 Deficiency Preserves Endothelial Function and Glycocalyx Integrity in Early Streptozotocin-Induced Diabetes

“…Diabetes is a well-known aggressor of the glomerular glycocalyx and endothelial barrier, resulting in loss of permselectivity and ultrafiltration of albumin (42). Glycocalyx damage coincides with microalbuminuria in type 1 diabetes (15).…”

The phenomenon of focal segmental glomerulosclerosis post-transplantation—a one-hit wonder?

“…To accomplish this, the 'factor' needs to breach the endothelial glycocalyx [10], the endothelial cell and the glomerular basement membrane. TNF-α is a 51-kDa homotrimer and therefore smaller than albumin, but its filtration properties would depend largely on its properties, such as shape, deformability and charge [11].…”

Translational research into vascular wall function: regulatory effects of systemic and specific factors

“…It is an essential initial stage in diabetes mellitus-related micrangiopathies and chronic venous diseases [17]. Ischemia/reperfusion, infection, diabetes and renal failure induce glycocalyx destruction [18][19][20]. A decrease in its volume occurring in hyperglycemia increases vulnerability of blood vessels and is associated with endothelial dysfunction (elevation of plasma hyaluronan) and coagulation activation in vivo (high blood contents of 1+2 prothrombin fragment and D-dimer of fibrin) [21].…”