Heparan sulphate in the pathogenesis of diabetic nephropathy

Kofoed‐Enevoldsen, Allan

doi:10.1002/dmr.5610110205

Cited by 14 publications

(9 citation statements)

References 132 publications

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“…the human diabetic kidney [2,4] and decreased Ndeacetylation/N-sulfation has been noted in the diabetic rat [3].…”

Section: Conclusion/interpretationmentioning

confidence: 90%

“…Of particular interest in this regard are changes in the GBM heparan sulphate which serves as an important anionic component of the renal filtration barrier [3]; both biochemical and immunochemical measurements of the heparan sulphate proteoglycan and its glycosaminoglycan chains have shown a reduction in Abstract Aims/hypothesis. Heparan sulphate proteoglycan is an important component of the glomerular anionic filtration barrier and its reduced amount in diabetes contributes to glomerular dysfunction.…”

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confidence: 99%

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A specific structural alteration in the heparan sulphate of human glomerular basement membrane in diabetes

Spiro

2000

Diabetologia

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The alterations affecting the macromolecules of the glomerular basement membrane and adjoining mesangium (GBM) are believed to have a major role in the glomerular dysfunction of diabetes. Both collagenous and noncollagenous components of the glomerular filtration barrier have been shown to undergo biochemical derangements in this disease which contribute to the renal pathophysiology [1±3].Of particular interest in this regard are changes in the GBM heparan sulphate which serves as an important anionic component of the renal filtration barrier [3]; both biochemical and immunochemical measurements of the heparan sulphate proteoglycan and its glycosaminoglycan chains have shown a reduction in Abstract Aims/hypothesis. Heparan sulphate proteoglycan is an important component of the glomerular anionic filtration barrier and its reduced amount in diabetes contributes to glomerular dysfunction. The objective of this study was to determine if there is also an alteration in the sulphation pattern of the diabetic heparan sulphate chains. Methods. The heparan sulphate in the glomerular basement membrane/mesangial matrix from human diabetic and nondiabetic kidneys obtained at autopsy was fragmented by a hydrazine/nitrous acid procedure and after radiolabelling with NaB[ 3 H] 4 , the disaccharide products were chromatographically resolved and quantified. Results. Six sulphated disaccharides were identified in both the diabetic and nondiabetic samples and the molar distribution of these was similar, with the notable exception of the iduronic acid-2-O-sulphatea1 ® 4glucosamine-3-O-sulphate species which occurred in the diabetic glomeruli in less than half the amount as in the nondiabetic samples (9.0 % compared to 18.7 % of total sulphated disaccharides, p < 0.005). Conclusion/interpretation.3-O-sulphated glucosamine is a rare constituent of heparan sulphate occurring usually in a glucuronic acidb1 ® 4glu-cosamine-3-O-sulphate( 6-O-sulphate) sequence within the antithrombin-binding domain. In the glomerular basement membrane where the 3-O-sulphated glucosamine is present in substantial amounts, however, it occurs exclusively in an iduronic acid-containing sequence. It is likely that the recently discovered 3-O-sulphotransferase variant which specifically acts on the iduronic acida1 ® 4glucosamine sequence is decreased in human diabetes and moreover that this unusual disaccharide could be a component of a specific heparan sulphate domain which interacts with bioactive proteins. [Diabetologia (2000

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“…the human diabetic kidney [2,4] and decreased Ndeacetylation/N-sulfation has been noted in the diabetic rat [3].…”

Section: Conclusion/interpretationmentioning

confidence: 90%

mentioning

confidence: 99%

A specific structural alteration in the heparan sulphate of human glomerular basement membrane in diabetes

Spiro

2000

Diabetologia

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“…The HS chains are modified post-transcriptionally by N-substitution of the glucosamine units, facilitated by the key enzyme glucosaminyl N-deacetylase/N-sulphotransferase. A reduction in this enzyme has been found in diabetes [24]. Thus, loss of HS staining might be explained by a reduction in N-unsubstituted glucosamine units of HS or an absolute reduction in HS.…”

Section: Discussionmentioning

confidence: 99%

Extracellular matrix in human diabetic nephropathy: reduced expression of heparan sulphate in skin basement membrane

et al. 1998

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In Type 1 diabetes mellitus all tissues are exposed to hyperglycaemia, but only a subset (30±40 %) of diabetic patients develop diabetic kidney disease [1,2]. According to the Steno hypothesis, albuminuria and associated complications result from a genetic polymorphism of enzymes involved in the metabolism of heparan sulphate proteoglycans (HSPG) [2].HSPG consists of a core protein with heparan sulphate (HS) glycosaminoglycan side chains. Sulphate Diabetologia (1998) Summary In diabetic nephropathy, expression of glycosaminoglycan side chains of heparan sulphate proteoglycan in the glomerular basement membrane is reduced proportionally to the degree of proteinuria. We performed a cross-sectional study to evaluate whether non-vascular basement membranes also show a decrease in heparan sulphate side chain staining in patients with diabetic nephropathy. We evaluated the skin basement membrane for extracellular matrix components in the following groups: control subjects (n = 16); patients with Type 1 diabetes and normoalbuminuria (n = 17), microalbuminuria (n = 7), and macroalbuminuria (n = 16); patients with Type 1 diabetes and diabetic nephropathy undergoing renal replacement therapy (n = 13); and non-diabetic patients undergoing renal replacement therapy (n = 21). The following antibodies were used for this immunohistochemical study: monoclonal antibodies against the heparan sulphate side chain (JM403) and core protein (JM72) of the glomerular heparan sulphate proteoglycan; polyclonal antibodies against the core protein (B31); polyclonal antibodies against collagen types I, III, and IV, fibronectin, and laminin; and monoclonal antibodies against the noncollagenous domain of a1(collagen IV) and a3(collagen IV), against transforming growth factor b(2G7), and against advanced glycosylation end products (4G9). Expression of heparan sulphate side chains was reduced in the skin basement membrane of patients with overt diabetic nephropathy, of those with Type 1 diabetes undergoing renal replacement therapy, and those with non-diabetic renal failure. Increased intensity of staining was found for collagen type I and advanced glycosylation end products in patients with diabetic nephropathy. Changes in the extracellular matrix of the skin basement membrane seem to be similar to those in the glomerular basement membrane. These findings support the suggestion that patients with diabetic nephropathy also have altered heparan sulphate and collagen staining in extrarenal basement membranes. However, patients with non-diabetic renal failure also had reduced expression of heparan sulphate in the skin basement membrane, suggesting that this finding is not specific for diabetic nephropathy. [Diabetologia (1998) Keywords Advanced glycosylation end products, albuminuria, basement membrane, collagen, Type 1 diabetes mellitus, diabetic nephropathy, epidermodermal junction basement membrane zone, fibroblasts, heparitin sulphate, skin.Received: 13 November 1997 and in revised form: 10 February 1998Corresponding author: Dr. J. W. van de...

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“…Development of glomerular lesions in diabetic nephropathy, especially mesangial expansion, leads to a reduced filtration surface with increased systemic blood pressure and increased urinary leakage of proteins. Kofed‐Envaldsen reported that there was evidence of charge selective glomerular capillary wall defects in albuminuric patients with insulin dependent diabetes mellitus (IDDM) 19 . Furthermore, Pedrinelli et al .…”

Section: Discussionmentioning

confidence: 99%

“…Kofed-Envaldsen reported that there was evidence of charge selective glomerular capillary wall defects in albuminuric patients with insulin dependent diabetes mellitus (IDDM). 19 Furthermore, Pedrinelli et al showed that endothelial dysfunction had a correlation with urinary excretion of albumin in essential hypertension, and that albuminuria might reflect a systemic dysfunction of vascular endothelium. 20 Laurens et al reported that direct podocyte damage led to albuminuria in vivo in rat.…”

Section: Discussionmentioning

confidence: 99%

Glomerular dysfunction, independent of tubular dysfunction, induced by antineoplastic chemotherapy in children

Ikarashi

Kakihara

Imai

et al. 2004

Pediatrics International

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Heparan sulphate in the pathogenesis of diabetic nephropathy

Cited by 14 publications

References 132 publications

A specific structural alteration in the heparan sulphate of human glomerular basement membrane in diabetes

A specific structural alteration in the heparan sulphate of human glomerular basement membrane in diabetes

Extracellular matrix in human diabetic nephropathy: reduced expression of heparan sulphate in skin basement membrane

Glomerular dysfunction, independent of tubular dysfunction, induced by antineoplastic chemotherapy in children

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