The endothelial glycocalyx as a potential modifier of the hemolytic uremic syndrome.
Atypical hemolytic uremic syndrome (HUS) is a renal disease due to complement dysregulation. Many of the known causes of atypical HUS originate from genetic mutations of complement regulatory proteins, such as complement factor H (CFH) and thrombomodulin. However, atypical HUS has only a genetic penetrance of 40-50% of the cases and usually appears in adulthood. We introduce a novel factor that may be involved in the onset and development of atypical HUS, i.e. the endothelial surface glycocalyx. The glycocalyx is a highly interactive matrix covering the luminal side of vascular endothelial cells and consists of glycosaminoglycans, proteoglycans and glycoproteins, which has an important role in maintaining homeostasis of the vasculature. The surface-bound glycocalyx glycosaminoglycan constituent heparan sulfate is crucial for CFH binding and function, both in recognition of host tissue and prevention of spontaneous complement activation via the alternative pathway. Most of the clinically relevant genetic mutations in CFH result in incorrect binding to heparan sulfate. In addition, a role between proper function of thrombomodulin and the endothelial glycocalyx has also been observed. We suggest that not only changes in binding properties of the complement regulatory proteins play a role but also changes in the endothelial glycocalyx are involved in increased risk of clinical manifestation of atypical HUS. Finally, vascular glycocalyx heterogeneity in turn could dictate the specific vulnerability of the glomerular vascular bed in atypical HUS and may provide new therapeutic targets to intervene with endothelial cell activation and local complement pathway regulation.
Department of Nephrology, Einthoven Laboratory for Vascular Medicine, Leiden University Medical Center, PO Box 9600, 2300 RC, Leiden, The Netherlands.
Margien G S
MG
Boels
Dae Hyun
DH
Lee
Bernard M
BM
van den Berg
Martijn J C
MJ
Dane
Johan
J
van der Vlag
Ton J
TJ
Rabelink
D065766:Atypical Hemolytic Uremic Syndrome; D003167:Complement Activation / Q000235:genetics / Q000276:immunology*; D017242:Complement Factor H / Q000235:genetics / Q000276:immunology*; D004730:Endothelium, Vascular / Q000276:immunology*; D020022:Genetic Predisposition to Disease; D019276:Glycocalyx / Q000276:immunology*; D006463:Hemolytic-Uremic Syndrome / Q000235:genetics / Q000276:immunology*; D019812:Heparan Sulfate Proteoglycans / Q000502:physiology*; D006801:Humans; D018180:Thrombomodulin / Q000235:genetics
D019812:Heparan Sulfate Proteoglycans; D018180:Thrombomodulin; D017242:Complement Factor H
Atypical hemolytic uremic syndrome; Complement factor H; Glycocalyx; Heparan sulfate proteoglycan; Thrombomodulin