Glomerular heparan sulfate alterations: Mechanisms and relevance for proteinuria

Abstract

Glomerular heparan sulfate alterations: Mechanisms and rele-During glomerular ultrafiltration, the barrier restrictvance for proteinuria. Heparan sulfate (HS) is the anionic ing the passage of plasma proteins into the urine is the polysaccharide side chain of HS proteoglycans (HSPGs) presglomerular capillary wall (GCW). The GCW consists of ent in basement membranes, in extracellular matrix, and on the fenestrated endothelium, the glomerular basement cell surfaces. Recently, agrin was identified as a major HSPG membrane (GBM), and the foot processes of the glomerpresent in the glomerular basement membrane (GBM). An increased permeability of the GBM for proteins after digestion ular visceral epithelial cells or podocytes with in-between of HS by heparitinase or after antibody binding to HS demonthe slit diaphragms. The fenestrae of the endothelial cells strated the importance of HS for the permselective properties allow direct contact of blood with the GBM and hardly of the GBM. With recently developed antibodies directed restrict passage of macromolecules [1]. Some data show against the GBM HSPG (agrin) core protein and the HS side that podocytes are involved in the permeability of the chain, we demonstrated a decrease in HS staining in the GBM in different human proteinuric glomerulopathies, such as sys-GCW. Cross-linking of the integrin receptors for extratemic lupus erythematosus (SLE), minimal change disease, cellular matrix (ECM) components on the podocyte remembranous glomerulonephritis, and diabetic nephropathy, sulted in a decreased adhesion of podocytes to the GBM whereas the staining of the agrin core protein remained unaland an increased passage of macromolecules in vitro [2]. tered. This suggested changes in the HS side chains of HSPG in proteinuric glomerular diseases. To gain more insight into Furthermore, in saponin-induced podocyte injury in the the mechanisms responsible for this observation, we studied single nephron model, passage of albumin through the GBM HS(PG) expression in experimental models of protein-GCW was localized to regions of detachment [3]. An uria. Similar HS changes were found in murine lupus nephritis, injection of a monoclonal antibody directed against a adriamycin nephropathy, and active Heymann nephritis. In component of the slit diaphragm resulted in an acute these models, an inverse correlation was found between HS staining in the GBM and proteinuria. From these investigamassive proteinuria [4, 5]. Nevertheless, the GBM is tions, four new and different mechanisms have emerged. First, probably the most important component of this barrier in lupus nephritis, HS was found to be masked by nucleosomes and restricts the passage of macromolecules by both size complexed to antinuclear autoantibodies. This masking was and charge. Tracer studies have shown that the GCW due to the binding of cationic moieties on the N-terminal parts behaves like a sieve, through which small molecules, of the core histones to anionic determinants in HS. Second, in adriamycin nephropathy, glomerular HS...

Critical comparative analyses of anti–α‐actinin and glomerulus‐bound antibodies in human and murine lupus nephritis

“…Consistent with this is the observation that nonpurified nucleosome-contaminated DNA6 or 452s46 antidsDNA antibodies bound DNA and nucleosomes, but not H1. None of the mAb or antibodies eluted from kidneys bound type IV collagen, heparan sulfate, or DNase I, which are known to bind nucleosomes (14,16,38) or DNA (35). Such results support the conclusion that these IgG antibodies recognize dsDNA and H1 by their variable regions.…”

“…It is unlikely that nucleosomes, if bound to these antibodies, could mediate binding to both anionic (DNA) and cationic (H1) structures. Nucleosomes are reported to bind anionic heparan sulfate or type IV collagen through protruding tails of cationic histones (16,25,38). In this respect, anti-dsDNA antibody-bound nucleosomes should be repelled by H1 rather than bound to it.…”

Reactive oxygen species mediate high glucose-induced heparanase-1 production and heparan sulphate proteoglycan degradation in human and rat endothelial cells: a potential role in the pathogenesis of atherosclerosis

“…Together, these observations suggest that ROS play a critical role in mediating high glucose-induced HPR1 production. It should be noted that ROS are also capable of directly shedding off heparan sulphate side chains by heparan sulphate depolymerisation [38,39]. Our experiment in Fig.…”

The Number of Podocyte Slit Diaphragms Is Decreased in Minimal Change Nephrotic Syndrome

“…Defects in the GBM and especially reduction of its anionic charge have been suggested to explain the leakage of negatively charged plasma proteins into urine in some disorders (2). On the other hand, detachment of the podocyte foot processes from the GBM has correlated with the onset of proteinuria in animal models (15).…”

“…Normally, water and small plasma solutes filtrate easily through this sieve but the passage of proteins with the size of albumin and larger is almost completely restricted. The GBM has been thought to be the most important component in this size and charge selective sieving, and defects in the GBM have been regarded responsible for proteinuria in many glomerular diseases (2). Recent findings, however, have challenged the central role of the GBM in nephrotic diseases (3,4).…”