Hemolysis is associated with altered heparan sulfate of the endothelial glycocalyx and with local complement activation in thrombotic microangiopathies.
Humans
Glycocalyx
/ metabolism
Hemolysis
Endothelial Cells
/ metabolism
Retrospective Studies
Thrombotic Microangiopathies
Complement Activation
/ genetics
Atypical Hemolytic Uremic Syndrome
Complement System Proteins
/ metabolism
Kidney Diseases
/ metabolism
Heparitin Sulfate
/ metabolism
Heme
/ metabolism
complement system
glycocalyx
heme
hemolytic uremic syndrome
heparan sulfate
thrombotic microangiopathy
Journal
Kidney international
ISSN: 1523-1755
Titre abrégé: Kidney Int
Pays: United States
ID NLM: 0323470
Informations de publication
Date de publication:
08 2023
08 2023
Historique:
received:
22
05
2022
revised:
03
03
2023
accepted:
24
03
2023
medline:
24
7
2023
pubmed:
11
5
2023
entrez:
10
5
2023
Statut:
ppublish
Résumé
The complement system plays a key role in the pathophysiology of kidney thrombotic microangiopathies (TMA), as illustrated by atypical hemolytic uremic syndrome. But complement abnormalities are not the only drivers of TMA lesions. Among other potential pathophysiological actors, we hypothesized that alteration of heparan sulfate (HS) in the endothelial glycocalyx could be important. To evaluate this, we analyzed clinical and histological features of kidney biopsies from a monocentric, retrospective cohort of 72 patients with TMA, particularly for HS integrity and markers of local complement activation. The role of heme (a major product of hemolysis) as an HS-degrading agent in vitro, and the impact of altering endothelial cell (ECs) HS on their ability to locally activate complement were studied. Compared with a positive control, glomerular HS staining was lower in 57 (79%) patients with TMA, moderately reduced in 20 (28%), and strongly reduced in 37 (51%) of these 57 cases. Strongly reduced HS density was significantly associated with both hemolysis at the time of biopsy and local complement activation (C3 and/or C5b-9 deposits). Using primary endothelial cells (HUVECs, Glomerular ECs), we observed decreased HS expression after short-term exposure to heme, and that artificial HS degradation by exposure to heparinase was associated with local complement activation. Further, prolonged exposure to heme modulated expression of several key genes of glycocalyx metabolism involved in coagulation regulation (C5-EPI, HS6ST1, HS3ST1). Thus, our study highlights the impact of hemolysis on the integrity of endothelial HS, both in patients and in endothelial cell models. Hence, acute alteration of HS may be a mechanism of heme-induced complement activation.
Identifiants
pubmed: 37164260
pii: S0085-2538(23)00327-7
doi: 10.1016/j.kint.2023.03.039
pii:
doi:
Substances chimiques
Complement System Proteins
9007-36-7
Heparitin Sulfate
9050-30-0
Heme
42VZT0U6YR
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
353-366Informations de copyright
Copyright © 2023 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.