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Titolo:
Glomerular heparan sulfate alterations: Mechanisms and relevance for proteinuria
Autore:
Raats, CJI; van den Born, J; Berden, JHM;
Indirizzi:
Univ Nijmegen St Radboud Hosp, Div Nephrol, NL-6500 HB Nijmegen, Netherlands Univ Nijmegen St Radboud Hosp Nijmegen Netherlands NL-6500 HB etherlands
Titolo Testata:
KIDNEY INTERNATIONAL
fascicolo: 2, volume: 57, anno: 2000,
pagine: 385 - 400
SICI:
0085-2538(200002)57:2<385:GHSAMA>2.0.ZU;2-W
Fonte:
ISI
Lingua:
ENG
Soggetto:
SUBENDOTHELIAL EXTRACELLULAR-MATRIX; FIBROBLAST GROWTH-FACTOR; DENSITY-LIPOPROTEIN-RECEPTOR; PROTEOGLYCAN CORE PROTEIN; MURINE LUPUS NEPHRITIS; BASEMENT-MEMBRANE GLYCOSAMINOGLYCANS; REACTIVE OXYGEN METABOLITES; DEPENDENT DIABETES-MELLITUS; GLUCOSAMINYL N-DEACETYLASE; DECREASED DENOVO SYNTHESIS;
Keywords:
glomerular basement membrane; protein permeability; extracellular matrix; podocytes; heparan sulfate proteoglycans;
Tipo documento:
Review
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
220
Recensione:
Indirizzi per estratti:
Indirizzo: Berden, JHM Univ Nijmegen St Radboud Hosp, Div Nephrol, POB 9101, NL-6500 HB Nijmegen,Netherlands Univ Nijmegen St Radboud Hosp POB 9101 Nijmegen Netherlands NL-6500 HB
Citazione:
C.J.I. Raats et al., "Glomerular heparan sulfate alterations: Mechanisms and relevance for proteinuria", KIDNEY INT, 57(2), 2000, pp. 385-400

Abstract

Heparan sulfate (HS) is the anionic polysaccharide side chain of HS proteoglycans (HSPGs) present in basement membranes, in extracellular matrix, andon cell surfaces. Recently, agrin was identified as a major HSPG present in the glomerular basement membrane (GBM). An increased permeability of the GBM for proteins after digestion of HS by heparitinase or after antibody binding to HS demonstrated the importance of HS for the permselective properties of the GBM. With recently developed antibodies directed against the GBMHSPG (agrin) core protein and the HS side chain, we demonstrated a decrease in HS staining in the GBM in different human proteinuric glomerulopathies, such as systemic lupus erythematosus (SLE), minimal change disease, membranous glomerulonephritis, and diabetic nephropathy, whereas the staining ofthe agrin core protein remained unaltered. This suggested changes in the HS side chains of HSPG in proteinuric glomerular diseases. To gain more insight into the mechanisms responsible for this observation, we studied GBM HS(PG) expression in experimental models of proteinuria. Similar HS changes were found in murine lupus nephritis, adriamycin nephropathy, and active Heymann nephritis. In these models, an inverse correlation was found between HS staining in the GBM and proteinuria. From these investigations, four new and different mechanisms have emerged. First, in lupus nephritis, HS was found to be masked by nucleosomes complexed to antinuclear autoantibodies. This masking was due to the binding of cationic moieties on the N-terminal parts of the core histones to anionic determinants in HS. Second, in adriamycin nephropathy, glomerular HS was depolymerized by reactive oxygen species (ROS), mainly hydroxyl radicals, which could be prevented by scavengers both in vitro (exposure of HS to ROS) and in vivo. Third, in vivo renal perfusion of purified elastase led to a decrease of HS in the GBM caused by proteolytic cleavage of the agrin core protein near the attachment sites of HS by the MS-bound enzyme. Fourth, in streptozotocin-induced diabetic nephropathy and during culture of glomerular cells under high glucose conditions, evidence was obtained that hyperglycemia led to a down-regulation of HS synthesis, accompanied by a reduction in the degree of HS sulfation.

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Documento generato il 11/07/20 alle ore 20:38:59