Glomerular endothelial glycocalyx-derived heparan sulfate inhibits glomerular leukocyte influx and attenuates experimental glomerulonephritis
Proliferative forms of glomerulonephritis are characterized by the influx of leukocytes, albuminuria, and loss of kidney function. The glomerular endothelial glycocalyx is a thick carbohydrate layer that covers the endothelium and is comprised of heparan sulfate (HS), which plays a pivotal role in g...
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Frontiers Media S.A.
2023-06-01
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| Series: | Frontiers in Molecular Biosciences |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fmolb.2023.1177560/full |
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| author | Marissa L. Maciej-Hulme Jasper J. Van Gemst Patience Sanderson Angelique L. W. M. M. Rops Jo H. Berden Bart Smeets I. Jonathan Amster Ton J. Rabelink Johan Van Der Vlag |
| author_facet | Marissa L. Maciej-Hulme Jasper J. Van Gemst Patience Sanderson Angelique L. W. M. M. Rops Jo H. Berden Bart Smeets I. Jonathan Amster Ton J. Rabelink Johan Van Der Vlag |
| author_sort | Marissa L. Maciej-Hulme |
| collection | DOAJ |
| description | Proliferative forms of glomerulonephritis are characterized by the influx of leukocytes, albuminuria, and loss of kidney function. The glomerular endothelial glycocalyx is a thick carbohydrate layer that covers the endothelium and is comprised of heparan sulfate (HS), which plays a pivotal role in glomerular inflammation by facilitating endothelial-leukocyte trafficking. We hypothesize that the exogenous glomerular glycocalyx may reduce the glomerular influx of inflammatory cells during glomerulonephritis. Indeed, administration of mouse glomerular endothelial cell (mGEnC)-derived glycocalyx constituents, or the low-molecular-weight heparin enoxaparin, reduced proteinuria in mice with experimental glomerulonephritis. Glomerular influx of granulocytes and macrophages, as well as glomerular fibrin deposition, was reduced by the administration of mGEnC-derived glycocalyx constituents, thereby explaining the improved clinical outcome. HSglx also inhibited granulocyte adhesion to human glomerular endothelial cells in vitro. Notably, a specific HSglx fraction inhibited both CD11b and L-selectin binding to activated mGEnCs. Mass spectrometry analysis of this specific fraction revealed six HS oligosaccharides, ranging from tetra- to hexasaccharides with 2–7 sulfates. In summary, we demonstrate that exogenous HSglx reduces albuminuria during glomerulonephritis, which is possibly mediated via multiple mechanisms. Our results justify the further development of structurally defined HS-based therapeutics for patients with (acute) inflammatory glomerular diseases, which may be applicable to non-renal inflammatory diseases as well. |
| first_indexed | 2024-03-13T08:06:11Z |
| format | Article |
| id | doaj.art-5060c46b8253413ba7b4953347efe22b |
| institution | Directory Open Access Journal |
| issn | 2296-889X |
| language | English |
| last_indexed | 2024-03-13T08:06:11Z |
| publishDate | 2023-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Biosciences |
| spelling | doaj.art-5060c46b8253413ba7b4953347efe22b2023-06-01T05:07:59ZengFrontiers Media S.A.Frontiers in Molecular Biosciences2296-889X2023-06-011010.3389/fmolb.2023.11775601177560Glomerular endothelial glycocalyx-derived heparan sulfate inhibits glomerular leukocyte influx and attenuates experimental glomerulonephritisMarissa L. Maciej-Hulme0Jasper J. Van Gemst1Patience Sanderson2Angelique L. W. M. M. Rops3Jo H. Berden4Bart Smeets5I. Jonathan Amster6Ton J. Rabelink7Johan Van Der Vlag8Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, NetherlandsDepartment of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, NetherlandsDepartment of Chemistry, University of Georgia, Athens, GA, United StatesDepartment of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, NetherlandsDepartment of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, NetherlandsDepartment of Pathology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, NetherlandsDepartment of Chemistry, University of Georgia, Athens, GA, United StatesDepartment of Nephrology, Einthoven Laboratory for Vascular Medicine, Leiden University Medical Center, Leiden, NetherlandsDepartment of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, NetherlandsProliferative forms of glomerulonephritis are characterized by the influx of leukocytes, albuminuria, and loss of kidney function. The glomerular endothelial glycocalyx is a thick carbohydrate layer that covers the endothelium and is comprised of heparan sulfate (HS), which plays a pivotal role in glomerular inflammation by facilitating endothelial-leukocyte trafficking. We hypothesize that the exogenous glomerular glycocalyx may reduce the glomerular influx of inflammatory cells during glomerulonephritis. Indeed, administration of mouse glomerular endothelial cell (mGEnC)-derived glycocalyx constituents, or the low-molecular-weight heparin enoxaparin, reduced proteinuria in mice with experimental glomerulonephritis. Glomerular influx of granulocytes and macrophages, as well as glomerular fibrin deposition, was reduced by the administration of mGEnC-derived glycocalyx constituents, thereby explaining the improved clinical outcome. HSglx also inhibited granulocyte adhesion to human glomerular endothelial cells in vitro. Notably, a specific HSglx fraction inhibited both CD11b and L-selectin binding to activated mGEnCs. Mass spectrometry analysis of this specific fraction revealed six HS oligosaccharides, ranging from tetra- to hexasaccharides with 2–7 sulfates. In summary, we demonstrate that exogenous HSglx reduces albuminuria during glomerulonephritis, which is possibly mediated via multiple mechanisms. Our results justify the further development of structurally defined HS-based therapeutics for patients with (acute) inflammatory glomerular diseases, which may be applicable to non-renal inflammatory diseases as well.https://www.frontiersin.org/articles/10.3389/fmolb.2023.1177560/fullheparan sulfateglomerulonephritisleukocyteglomerular endothelial cellinflammationglycocalyx |
| spellingShingle | Marissa L. Maciej-Hulme Jasper J. Van Gemst Patience Sanderson Angelique L. W. M. M. Rops Jo H. Berden Bart Smeets I. Jonathan Amster Ton J. Rabelink Johan Van Der Vlag Glomerular endothelial glycocalyx-derived heparan sulfate inhibits glomerular leukocyte influx and attenuates experimental glomerulonephritis Frontiers in Molecular Biosciences heparan sulfate glomerulonephritis leukocyte glomerular endothelial cell inflammation glycocalyx |
| title | Glomerular endothelial glycocalyx-derived heparan sulfate inhibits glomerular leukocyte influx and attenuates experimental glomerulonephritis |
| title_full | Glomerular endothelial glycocalyx-derived heparan sulfate inhibits glomerular leukocyte influx and attenuates experimental glomerulonephritis |
| title_fullStr | Glomerular endothelial glycocalyx-derived heparan sulfate inhibits glomerular leukocyte influx and attenuates experimental glomerulonephritis |
| title_full_unstemmed | Glomerular endothelial glycocalyx-derived heparan sulfate inhibits glomerular leukocyte influx and attenuates experimental glomerulonephritis |
| title_short | Glomerular endothelial glycocalyx-derived heparan sulfate inhibits glomerular leukocyte influx and attenuates experimental glomerulonephritis |
| title_sort | glomerular endothelial glycocalyx derived heparan sulfate inhibits glomerular leukocyte influx and attenuates experimental glomerulonephritis |
| topic | heparan sulfate glomerulonephritis leukocyte glomerular endothelial cell inflammation glycocalyx |
| url | https://www.frontiersin.org/articles/10.3389/fmolb.2023.1177560/full |
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