Modulation of heparan sulfate in the glomerular endothelial glycocalyx decreases leukocyte influx during experimental glomerulonephritis.
The glomerular endothelial glycocalyx is postulated to be an important modulator of permeability and inflammation. The glycocalyx consists of complex polysaccharides, the main functional constituent of which, heparan sulfate (HS), is synthesized and modified by multiple enzymes. The N-deacetylase-N-sulfotransferase (Ndst) enzymes initiate and dictate the modification process. Here we evaluated the effects of modulation of HS in the endothelial glycocalyx on albuminuria and glomerular leukocyte influx using mice deficient in endothelial and leukocyte Ndst1 (TEKCre+/Ndst1flox/flox). In these mice, glomerular expression of a specific HS domain was significantly decreased, whereas the expression of other HS domains was normal. In the endothelial glycocalyx, this specific HS structure was not associated with albuminuria or with changes in renal function. However, glomerular leukocyte influx was significantly reduced during antiglomerular basement membrane nephritis, which was associated with less glomerular injury and better renal function. In vitro decreased adhesion of wild-type and Ndst1-deficient granulocytes to Ndst1-silenced glomerular endothelial cells was found, accompanied by a decreased binding of chemokines and L-selectin. Thus, modulation of HS in the glomerular endothelial glycocalyx significantly reduced the inflammatory response in antiglomerular basement membrane nephritis.
Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands.
Angelique L W M M
AL
Rops
Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands.
Markus A
MA
Loeven
Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands.
Jasper J
JJ
van Gemst
Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands.
Iris
I
Eversen
Department of Cellular and Molecular Medicine, Glycobiology Research and Training Center, University of California, California, USA.
Xander M
XM
Van Wijk
Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands.
Henry B
HB
Dijkman
Department of Biochemistry, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands.
Toin H
TH
van Kuppevelt
Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands.
Jo H M
JH
Berden
Department of Nephrology and Einthoven Laboratory for Vascular Medicine, Leiden University Medical Centre, Leiden, The Netherlands.
Ton J
TJ
Rabelink
Department of Cellular and Molecular Medicine, Glycobiology Research and Training Center, University of California, California, USA.
Jeffrey D
JD
Esko
Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands.
Johan
J
van der Vlag
D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control; D001323:Autoantibodies; D002448:Cell Adhesion; D002460:Cell Line; D018925:Chemokines / Q000378:metabolism; D002634:Chemotaxis, Leukocyte; D018920:Coculture Techniques; D004195:Disease Models, Animal; D015536:Down-Regulation; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism*; D005260:Female; D019276:Glycocalyx / Q000276:immunology / Q000378:metabolism*; D006497:Heparan Sulfate / Q000378:metabolism*; D007678:Kidney Glomerulus / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D019041:L-Selectin / Q000378:metabolism; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D034622:RNA Interference; D015398:Signal Transduction; D015238:Sulfotransferases / Q000172:deficiency / Q000235:genetics; D013997:Time Factors; D014162:Transfection
D001323:Autoantibodies; D018925:Chemokines; D006497:Heparan Sulfate; D019041:L-Selectin; D015238:Sulfotransferases; C051951:antiglomerular basement membrane antibody; C021350:heparitin sulfotransferase