Cargando…

Glycosaminoglycans and fucoidan have a protective effect on experimental glomerulonephritis

Background: The glomerular endothelial glycocalyx is degraded during inflammation. The glycocalyx plays a pivotal role in endothelial function and is involved in many processes including binding of chemokines and cytokines, leukocyte trafficking, and preventing proteinuria. HS-based therapeutics are...

Descripción completa

Detalles Bibliográficos
Autores principales: Buijsers, Baranca, Maciej-Hulme, Marissa, Jacobs, Maaike, Bebber, Marinka Bakker-van, de Graaf, Mark, Salmenov, Rustem, Parr, Naomi, Rabelink, Ton J., Nijenhuis, Tom, van der Vlag, Johan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10354240/
https://www.ncbi.nlm.nih.gov/pubmed/37475889
http://dx.doi.org/10.3389/fmolb.2023.1223972
_version_ 1785074884466966528
author Buijsers, Baranca
Maciej-Hulme, Marissa
Jacobs, Maaike
Bebber, Marinka Bakker-van
de Graaf, Mark
Salmenov, Rustem
Parr, Naomi
Rabelink, Ton J.
Nijenhuis, Tom
van der Vlag, Johan
author_facet Buijsers, Baranca
Maciej-Hulme, Marissa
Jacobs, Maaike
Bebber, Marinka Bakker-van
de Graaf, Mark
Salmenov, Rustem
Parr, Naomi
Rabelink, Ton J.
Nijenhuis, Tom
van der Vlag, Johan
author_sort Buijsers, Baranca
collection PubMed
description Background: The glomerular endothelial glycocalyx is degraded during inflammation. The glycocalyx plays a pivotal role in endothelial function and is involved in many processes including binding of chemokines and cytokines, leukocyte trafficking, and preventing proteinuria. HS-based therapeutics are a promising novel class of anti-inflammatory drugs to restore a compromised endothelial glycocalyx under inflammatory conditions. Recently, we demonstrated that treatment with HS extracted from unstimulated glomerular endothelial glycocalyx (unstimulated HS(glx)) reduced albuminuria during anti-GBM induced glomerulonephritis. Since endothelial HS domains are distinct in unstimulated versus inflammatory conditions, we hypothesized that 1) unstimulated HS(glx), 2) LPS-stimulated HS(glx), 3) the HS-mimetic fucoidan and 4) the glycosaminoglycan preparation sulodexide, which is a mixture of low molecular weight heparin and dermatan sulfate, might have different beneficial effects in experimental glomerulonephritis. Methods: The effect of unstimulated HS(glx), LPS HS(glx), Laminaria japonica fucoidan, or sulodexide on experimental glomerulonephritis was tested in LPS-induced glomerulonephritis in mice. Analyses included urinary albumin creatinine measurement, cytokine expression in plasma and renal cortex, and renal influx of immune cells determined by flow cytometry and immunofluorescence staining. Furthermore, the observed in vivo effects were evaluated in cultured glomerular endothelial cells and peripheral blood mononuclear cells by measuring cytokine and ICAM-1 expression levels. The ability of the compounds to inhibit heparanase activity was assessed in a heparanase activity assay. Results: Treatment of mice with LPS HS(glx) or sulodexide near-significantly attenuated LPS-induced proteinuria. All treatments reduced plasma MCP-1 levels, whereas only fucoidan reduced IL-6 and IL-10 plasma levels. Moreover, all treatments reversed cortical ICAM-1 mRNA expression and both fucoidan and sulodexide reversed cortical IL-6 and nephrin mRNA expression. Sulodexide decreased renal influx of CD45(+) immune cells whereas renal influx of macrophages and granulocytes remained unaltered for all treatments. Although all compounds inhibited HPSE activity, fucoidan and sulodexide were the most potent inhibitors. Notably, fucoidan and sulodexide decreased LPS-induced mRNA expression of ICAM-1 and IL-6 by cultured glomerular endothelial cells. Conclusion: Our data show a potentially protective effect of glycosaminoglycans and fucoidan in experimental glomerulonephritis. Future research should be aimed at the further identification of defined HS structures that have therapeutic potential in the treatment of glomerular diseases.
format Online
Article
Text
id pubmed-10354240
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-103542402023-07-20 Glycosaminoglycans and fucoidan have a protective effect on experimental glomerulonephritis Buijsers, Baranca Maciej-Hulme, Marissa Jacobs, Maaike Bebber, Marinka Bakker-van de Graaf, Mark Salmenov, Rustem Parr, Naomi Rabelink, Ton J. Nijenhuis, Tom van der Vlag, Johan Front Mol Biosci Molecular Biosciences Background: The glomerular endothelial glycocalyx is degraded during inflammation. The glycocalyx plays a pivotal role in endothelial function and is involved in many processes including binding of chemokines and cytokines, leukocyte trafficking, and preventing proteinuria. HS-based therapeutics are a promising novel class of anti-inflammatory drugs to restore a compromised endothelial glycocalyx under inflammatory conditions. Recently, we demonstrated that treatment with HS extracted from unstimulated glomerular endothelial glycocalyx (unstimulated HS(glx)) reduced albuminuria during anti-GBM induced glomerulonephritis. Since endothelial HS domains are distinct in unstimulated versus inflammatory conditions, we hypothesized that 1) unstimulated HS(glx), 2) LPS-stimulated HS(glx), 3) the HS-mimetic fucoidan and 4) the glycosaminoglycan preparation sulodexide, which is a mixture of low molecular weight heparin and dermatan sulfate, might have different beneficial effects in experimental glomerulonephritis. Methods: The effect of unstimulated HS(glx), LPS HS(glx), Laminaria japonica fucoidan, or sulodexide on experimental glomerulonephritis was tested in LPS-induced glomerulonephritis in mice. Analyses included urinary albumin creatinine measurement, cytokine expression in plasma and renal cortex, and renal influx of immune cells determined by flow cytometry and immunofluorescence staining. Furthermore, the observed in vivo effects were evaluated in cultured glomerular endothelial cells and peripheral blood mononuclear cells by measuring cytokine and ICAM-1 expression levels. The ability of the compounds to inhibit heparanase activity was assessed in a heparanase activity assay. Results: Treatment of mice with LPS HS(glx) or sulodexide near-significantly attenuated LPS-induced proteinuria. All treatments reduced plasma MCP-1 levels, whereas only fucoidan reduced IL-6 and IL-10 plasma levels. Moreover, all treatments reversed cortical ICAM-1 mRNA expression and both fucoidan and sulodexide reversed cortical IL-6 and nephrin mRNA expression. Sulodexide decreased renal influx of CD45(+) immune cells whereas renal influx of macrophages and granulocytes remained unaltered for all treatments. Although all compounds inhibited HPSE activity, fucoidan and sulodexide were the most potent inhibitors. Notably, fucoidan and sulodexide decreased LPS-induced mRNA expression of ICAM-1 and IL-6 by cultured glomerular endothelial cells. Conclusion: Our data show a potentially protective effect of glycosaminoglycans and fucoidan in experimental glomerulonephritis. Future research should be aimed at the further identification of defined HS structures that have therapeutic potential in the treatment of glomerular diseases. Frontiers Media S.A. 2023-07-05 /pmc/articles/PMC10354240/ /pubmed/37475889 http://dx.doi.org/10.3389/fmolb.2023.1223972 Text en Copyright © 2023 Buijsers, Maciej-Hulme, Jacobs, Bebber, de Graaf, Salmenov, Parr, Rabelink, Nijenhuis and van der Vlag. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Molecular Biosciences
Buijsers, Baranca
Maciej-Hulme, Marissa
Jacobs, Maaike
Bebber, Marinka Bakker-van
de Graaf, Mark
Salmenov, Rustem
Parr, Naomi
Rabelink, Ton J.
Nijenhuis, Tom
van der Vlag, Johan
Glycosaminoglycans and fucoidan have a protective effect on experimental glomerulonephritis
title Glycosaminoglycans and fucoidan have a protective effect on experimental glomerulonephritis
title_full Glycosaminoglycans and fucoidan have a protective effect on experimental glomerulonephritis
title_fullStr Glycosaminoglycans and fucoidan have a protective effect on experimental glomerulonephritis
title_full_unstemmed Glycosaminoglycans and fucoidan have a protective effect on experimental glomerulonephritis
title_short Glycosaminoglycans and fucoidan have a protective effect on experimental glomerulonephritis
title_sort glycosaminoglycans and fucoidan have a protective effect on experimental glomerulonephritis
topic Molecular Biosciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10354240/
https://www.ncbi.nlm.nih.gov/pubmed/37475889
http://dx.doi.org/10.3389/fmolb.2023.1223972
work_keys_str_mv AT buijsersbaranca glycosaminoglycansandfucoidanhaveaprotectiveeffectonexperimentalglomerulonephritis
AT maciejhulmemarissa glycosaminoglycansandfucoidanhaveaprotectiveeffectonexperimentalglomerulonephritis
AT jacobsmaaike glycosaminoglycansandfucoidanhaveaprotectiveeffectonexperimentalglomerulonephritis
AT bebbermarinkabakkervan glycosaminoglycansandfucoidanhaveaprotectiveeffectonexperimentalglomerulonephritis
AT degraafmark glycosaminoglycansandfucoidanhaveaprotectiveeffectonexperimentalglomerulonephritis
AT salmenovrustem glycosaminoglycansandfucoidanhaveaprotectiveeffectonexperimentalglomerulonephritis
AT parrnaomi glycosaminoglycansandfucoidanhaveaprotectiveeffectonexperimentalglomerulonephritis
AT rabelinktonj glycosaminoglycansandfucoidanhaveaprotectiveeffectonexperimentalglomerulonephritis
AT nijenhuistom glycosaminoglycansandfucoidanhaveaprotectiveeffectonexperimentalglomerulonephritis
AT vandervlagjohan glycosaminoglycansandfucoidanhaveaprotectiveeffectonexperimentalglomerulonephritis