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 HSglx) reduced
albuminuria during
anti-GBM induced
glomerulonephritis. Since endothelial HS domains are distinct in unstimulated versus inflammatory conditions, we hypothesized that 1) unstimulated HSglx, 2) LPS-stimulated HSglx, 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 HSglx, LPS HSglx, 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 HSglx 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.