Syndecan-1 deficiency aggravates anti-glomerular basement membrane nephritis.
During the heterologous phase of experimental anti-glomerular basement membrane (anti-GBM) nephritis, leukocyte influx peaks within hours, whereas albuminuria occurs within 1 day. In the subsequent autologous phase, endogenous anti-GBM IgG develops and albuminuria persists. Heparan sulfate (HS) proteoglycans like syndecan-1 play multiple roles during inflammation and we evaluate its role in experimental anti-GBM disease using syndecan-1 knockout (sdc-1-/-) mice. During the heterologous phase, glomerular leukocyte/macrophage influx was significantly higher in the sdc-1-/- mice and this was associated with higher glomerular endothelial expression of specific HS domains. In the autologous phase, glomerular influx of CD4+/CD8+ T cells was higher in the sdc-1-/- mice and these mice had persistently higher albuminuria and serum creatinine levels than wild-type mice. This resulted in a more sever glomerular injury and increased expression of extracellular matrix proteins. The sdc-1-/- mice developed higher plasma levels and glomerular deposits of total mouse Ig and IgG1 anti-rabbit IgG, whereas the levels of mouse IgG2a anti-rabbit IgG were lower. Furthermore, decreased Th1 and higher Th2 renal cytokine/chemokine expression were found in the sdc-1-/- mice. Our studies show that syndecan-1 deficiency exacerbates anti-GBM nephritis shifting the Th1/Th2 balance towards a Th2 response.
Rops
A L
AL
Nephrology Research Laboratory, Division of Nephrology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Götte
M
M
Baselmans
M H
MH
van den Hoven
M J
MJ
Steenbergen
E J
EJ
Lensen
J F
JF
Wijnhoven
T J
TJ
Cevikbas
F
F
van den Heuvel
L P
LP
van Kuppevelt
T H
TH
Berden
J H
JH
van der Vlag
J
J
D000419:Albuminuria / Q000276:immunology / Q000473:pathology; D000818:Animals; D001485:Basement Membrane / Q000276:immunology* / Q000473:pathology; D016516:CD4-CD8 Ratio; D003404:Creatinine / Q000097:blood; D019084:Fluorescent Antibody Technique, Indirect; D007074:Immunoglobulin G / Q000097:blood; D007150:Immunohistochemistry; D007678:Kidney Glomerulus / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009393:Nephritis / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D011817:Rabbits; D053668:Syndecan-1 / Q000172:deficiency*; D018417:Th1 Cells / Q000378:metabolism; D018418:Th2 Cells / Q000378:metabolism