Modulation of heparan sulfate in the glomerular endothelial glycocalyx decreases leukocyte influx during experimental glomerulonephritis

• Published in: Kidney international Vol. 86; no. 5; pp. 932 - 942
• Main Authors: LWMM Rops, Angelique, Loeven, Markus A., van Gemst, Jasper J., Eversen, Iris, Van Wijk, Xander M., Dijkman, Henry B., van Kuppevelt, Toin H., Berden, Jo H.M., Rabelink, Ton J., Esko, Jeffrey D., van der Vlag, Johan
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2014; Elsevier Limited
• Subjects: acute kidney injury; Animals; anti-GBM disease; Anti-Glomerular Basement Membrane Disease - genetics; Anti-Glomerular Basement Membrane Disease - immunology; Anti-Glomerular Basement Membrane Disease - metabolism; Anti-Glomerular Basement Membrane Disease - physiopathology; Anti-Glomerular Basement Membrane Disease - prevention & control; Autoantibodies; Cell Adhesion; Cell Line; Chemokines - metabolism; Chemotaxis, Leukocyte; Coculture Techniques; Disease Models, Animal; Down-Regulation; Endothelial Cells - immunology; Endothelial Cells - metabolism; endothelium; Female; glomerular endothelial cells; glomerular filtration barrier; glomerulonephritis; glycocalyx; Glycocalyx - immunology; Glycocalyx - metabolism; heparan sulfate; Heparitin Sulfate - metabolism; Kidney Glomerulus - immunology; Kidney Glomerulus - metabolism; Kidney Glomerulus - physiopathology; L-Selectin - metabolism; Leukocytes - immunology; Leukocytes - metabolism; Male; Mice, Inbred C57BL; Mice, Knockout; RNA Interference; Signal Transduction; Sulfotransferases - deficiency; Sulfotransferases - genetics; Time Factors; Transfection; glycocalyx; endothelium; glomerular filtration barrier; heparan sulfate; anti-GBM disease; acute kidney injury; glomerular endothelial cells; glomerulonephritis
• ISSN: 0085-2538; 1523-1755
• DOI: 10.1038/ki.2014.115

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.