J Cell Mol Med
2018[Mar]; 22
(3
): 1769-1777
PMID29168342
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Cumulating evidences suggested an important role of sphingosine-1-phosphate (S1P)
and its receptors in regulating endothelial barrier integrity. Our previous study
revealed that the circulating S1P levels and renal expression of S1PRs correlated
with disease activity and renal damage in patients with antineutrophil
cytoplasmic antibody (ANCA)-associated vasculitis (AAV). This study investigated
the role of S1P and its receptors in myeloperoxidase (MPO)-ANCA-positive
IgG-mediated glomerular endothelial cell (GEnC) activation. The effect of S1P on
morphological alteration of GEnCs in the presence of MPO-ANCA-positive IgG was
observed. Permeability assay was performed to determine endothelial monolayer
activation in quantity. Both membrane-bound and soluble ICAM-1 and VCAM-1 levels
were measured. Furthermore, antagonists and/or agonists of various S1PRs were
employed to determine the role of different S1PRs. S1P enhanced MPO-ANCA-positive
IgG-induced disruption of tight junction and disorganization of cytoskeleton in
GEnCs. S1P induced further increase in monolayer permeability of GEnC monolayers
in the presence of MPO-ANCA-positive IgG. S1P enhanced MPO-ANCA-positive
IgG-induced membrane-bound and soluble ICAM-1/VCAM-1 up-regulation of GEnCs.
Soluble ICAM-1 levels in the supernatants of GEnCs stimulated by S1P and
MPO-ANCA-positive IgG increased upon pre-incubation of S1PR1 antagonist, while
pre-incubation of GEnCs with the S1PR1 agonist down-regulated sICAM-1 level.
Blocking S1PR2-4 reduced sICAM-1 levels in the supernatants of GEnCs stimulated
by S1P and MPO-ANCA-positive IgG. Pre-incubation with S1PR5 agonist could
increase sICAM-1 level in the supernatants of GEnC stimulated by S1P and
MPO-ANCA-positive IgG. S1P can enhance MPO-ANCA-positive IgG-mediated GEnC
activation through S1PR2-5.
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