Reduction of heparan sulphate-associated anionic sites in the glomerular basement membrane of rats with streptozotocin-induced diabetic nephropathy

Born, Jacob van den; Kraats, A.A. van; Bakker, Marinka A.H.; Assmann, K.J.M.; Dijkman, Henry; Laak, J.A.W.M. van der; Berden, Jo H. M.

doi:10.1007/bf00422365

Cited by 39 publications

(18 citation statements)

References 40 publications

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“…Diabetic rats received three times a week a low dose (1-1.5 IU) of bovine insulin (Ultralente; Novo, Copenhagen, Denmark) to maintain blood glucose between 20 and 25 mmol/liter. Rats were followed for their body weight, blood glucose, urine production, and albuminuria as described previously (15,16). After 5 months six control and six diabetic rats were sacrificed, and the kidneys were removed and weighed.…”

Section: Methodsmentioning

confidence: 99%

“…Animals-Diabetes was induced in male Wister-Münich rats by a single intravenous injection of 55 mg of streptozotocin/kg of body weight as described previously (15,16). Sexand age-matched rats served as controls.…”

Section: Methodsmentioning

confidence: 99%

“…However, these studies were performed in advanced stages of DNP. In a rat diabetes model resembling early human DNP, we documented a significant loss in HS-related anionic sites in the GBM; however, without loss of GBM HS (15,16). This suggested undersulfation of GBM HS as an early event in DNP (17).…”

mentioning

confidence: 97%

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No Change in Glomerular Heparan Sulfate Structure in Early Human and Experimental Diabetic Nephropathy

Born¹,

Pisa²,

Bakker³

et al. 2006

Journal of Biological Chemistry

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Heparan sulfate (HS) proteoglycans are major anionic glycoconjugates of the glomerular basement membrane and are thought to contribute to the permeability properties of the glomerular capillary wall. In this study we evaluated whether the development of (micro)albuminuria in early human and experimental diabetic nephropathy is related to changes in glomerular HS expression or structure. Using a panel of recently characterized antibodies, glomerular HS expression was studied in kidney biopsies of type I diabetic patients with microalbuminuria or early albuminuria and in rat renal tissue after 5 months diabetes duration. Glomerular staining, however, revealed no differences between control and diabetic specimens. A significant ( p < 0.05) ϳ60% increase was found in HS N-deacetylase activity, a key enzyme in HS sulfation reactions, in diabetic glomeruli. Structural analysis of glomerular HS after in vivo and in vitro radiolabeling techniques revealed no changes in HS N-sulfation or charge density. Also HS chain length, protein binding properties, as well as disaccharide composition did not differ between control and diabetic glomerular HS samples. These results indicate that in experimental and early human diabetic nephropathy, increased urinary albumin excretion is not caused by loss of glomerular HS expression or sulfation and suggest other mechanisms to be responsible for increased glomerular albumin permeability.One of the first signs of diabetic nephropathy (DNP) 2 is a discrete increase in urinary excretion of albumin called microalbuminuria (1, 2). In this early phase of DNP mainly the charge-dependent permeability of the glomerular capillary wall seems to be affected, while during progression to overt proteinuria also the size-dependent permeability becomes disturbed (3). These findings suggest an early loss of glomerular basement membrane (GBM) charge with a subsequent increase in pore size. This charge-dependent permeability of the GBM is probably related to the presence of anionic constituents of the GBM, mainly heparan sulfates (HS), the glycosaminoglycan side chains of heparan sulfate proteoglycans (HSPGs) (4). Some years ago, we identified agrin as a major HSPG present in the GBM (5, 6), using antibodies toward either the core protein or the HS polysaccharide side chains (7-9). The relevance of HS for the charge-dependent permeability is illustrated by several observations: (i) enzymatic removal of HS from the GBM leads to albuminuria (10); (ii) an acute selective albuminuria was induced in rats by a monoclonal antibody to HS (4); (iii) a reduction of HS expression in the GBM was documented in several human and experimental proteinuric glomerular diseases, which inversely correlated with proteinuria (11,12).In overt DNP, the expression of HS in the GBM was decreased and correlated with proteinuria (13,14). However, these studies were performed in advanced stages of DNP. In a rat diabetes model resembling early human DNP, we documented a significant loss in HS-related anionic sites in the GBM; howeve...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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No Change in Glomerular Heparan Sulfate Structure in Early Human and Experimental Diabetic Nephropathy

Born¹,

Pisa²,

Bakker³

et al. 2006

Journal of Biological Chemistry

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“…In lupus nephritis, masking of HS by autoantibodies complexed to nucleosomes is proposed as a mechanism for the decrease in HS staining and albuminuria (14). In human and experimental diabetic nephropathy, it was suggested that the decrease in HS staining was due to loss of HS from the GBM (15,16). These mechanisms, however, are not likely to occur in other glomerular diseases (13).…”

Section: Heparan Sulfate (Hs)mentioning

confidence: 99%

Hydroxyl Radicals Depolymerize Glomerular Heparan Sulfate in Vitro and in Experimental Nephrotic Syndrome

Raats

Bakker

Born

et al. 1997

Journal of Biological Chemistry

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105

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Heparan sulfate, the polysaccharide side chain of heparan sulfate proteoglycan, is important for the permselective properties of the glomerular basement membrane. In this report, we show a role for hydroxyl radicals in heparan sulfate degradation and an enhanced glomerular basement membrane permeability. First, in enzyme-linked immunosorbent assay, exposure of coated heparan sulfate (proteoglycan) to reactive oxygen species resulted in a ؎50% decrease of binding of a monoclonal antibody against heparan sulfate, whereas binding of an antibody against the core protein remained unaltered. Second, on polyacrylamide gel electrophoresis, the molecular weight of heparan sulfate exposed to radicals was reduced which indicates depolymerization. Both in enzyme-linked immunosorbent assay and gel electrophoresis, hydroxyl radicals are instrumental for heparan sulfate degradation as shown by the addition of various radical scavengers. Third, in an experimental model for human nephrotic syndrome (Adriamycin nephropathy in rats), glomerular basement membrane staining of two recently described anti-heparan sulfate antibodies (JM403 and KJ865) was reduced by 24 and 43%. Treatment of Adriamycin-exposed rats with the hydroxyl radical scavenger dimethylthiourea both reduced albuminuria by 37% (p < 0.01) and partly prevented loss of heparan sulfate staining by 53% (JM403) and 39% (KJ865) (p < 0.03). In contrast to the heparan sulfate side chains, the core protein expression and the extent of glycanation did not change in Adriamycin nephropathy. We conclude that glomerular basement membrane heparan sulfate is susceptible to depolymerization by hydroxyl radicals leading to loss of glomerular basement membrane integrity and albuminuria.Heparan sulfate (HS) 1 is the anionic polysaccharide side chain of heparan sulfate proteoglycan (HSPG) present in basement membranes, extracellular matrix, and on the cell surface of many (if not all) cell types (1-3). Several investigators have shown that HS plays an important role in the permselective properties of the glomerular basement membrane (GBM) (4, 5). Enzymatic digestion of HS by heparitinase resulted in an increased passage of native ferritin and albumin through the GBM (6, 7). Furthermore, intravenous injection of a monoclonal antibody (mAb) directed against HS induces acute, selective proteinuria in rats (8). A reduction in GBM HS-associated anionic sites was found with cationic probes in several human and experimental proteinuric glomerulopathies (9, 10). With recently developed antibodies directed against GBM HSPG core protein and the HS side chain (11, 12), we demonstrated a decrease in HS staining in the GBM in different human proteinuric glomerulopathies, whereas the staining of the HSPG core protein remained unaltered (13). The mechanism responsible for this observation remains to be elucidated. In lupus nephritis, masking of HS by autoantibodies complexed to nucleosomes is proposed as a mechanism for the decrease in HS staining and albuminuria (14). In human and experimental diabe...

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“…Diabetic nephropathy is associated with decreased glomerular synthesis of glycosaminoglycans (GAGs) (1)(2)(3)(4)(5)(6)(7). This results in a loss of negative charge of the basement membrane and thereby increased passage of albumin (8,9).…”

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confidence: 99%

Urinary Sulphated Glycosaminoglycans and Tamm-Horsfall Protein in Type 1 Diabetic Patients

Torffvit

1999

Scandinavian Journal of Urology and Nephrology

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Reduction of heparan sulphate-associated anionic sites in the glomerular basement membrane of rats with streptozotocin-induced diabetic nephropathy

Cited by 39 publications

References 40 publications

No Change in Glomerular Heparan Sulfate Structure in Early Human and Experimental Diabetic Nephropathy

No Change in Glomerular Heparan Sulfate Structure in Early Human and Experimental Diabetic Nephropathy

Hydroxyl Radicals Depolymerize Glomerular Heparan Sulfate in Vitro and in Experimental Nephrotic Syndrome

Urinary Sulphated Glycosaminoglycans and Tamm-Horsfall Protein in Type 1 Diabetic Patients

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