Aberrant proteoglycan composition of the glomerular basement membrane in a patient with Denys-Drash syndrome

Heuvel, L.P.W.J. van den; Westenend, Pj; Born, Jacob van den; Assmann, K.J.M.; Knoers, Nine V A M; Monnens, L.A.H.

doi:10.1093/ndt/10.12.2205

Cited by 12 publications

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“…In our study, the reduced GBM staining was observed even in glomeruli showing only mild glomerular changes, and persisted throughout the course of the disease. This is in accordance with previous observations of reduced GBM staining and/or content of HS chains in two DDS patients [13,23]. It suggests that the increased urinary excretion of HS (GAG) chains observed by several authors [13,23,24] more likely results from failure to attach HS (GAG) chains on core proteins than from increased HSPG turnover.…”

Section: Discussionsupporting

confidence: 92%

“…This is in accordance with previous observations of reduced GBM staining and/or content of HS chains in two DDS patients [13,23]. It suggests that the increased urinary excretion of HS (GAG) chains observed by several authors [13,23,24] more likely results from failure to attach HS (GAG) chains on core proteins than from increased HSPG turnover. Loss of HS GAG chains could play a role in the occurrence or the persistence of proteinuria in DMS.…”

Section: Discussionsupporting

confidence: 92%

“…However, contrary to previous findings [8], we observed normal GBM staining with anti-HS (GAG) chain antibodies in minimal change disease. Staining was also normal in congenital nephrotic syndrome of the Finnish type, a finding consistent with immunohistological and biochemical studies showing normal GBM distribution and concentration of HS in patients with this disease [13,26]. The recently identified molecular defect in this disease does not involve a basement membrane protein but a podocyte-specific transmembrane protein named nephrin, expected to play a major role in maintaining the integrity of podocyte foot processes [27].…”

Section: Discussionsupporting

confidence: 81%

“…These proteins and their different isoforms have a precise pattern of distribution within the two regions of the glomerular ECM, the GBM and the glomerular mesangial matrix (GMM) [7,8,9,10,11]. Massive accumulation of extracellular material characterizes DMS and, to date, immunohistochemical analysis of the glomerular ECM has been performed only in three ESRD patients on autopsy or nephrectomy specimens [12,13]. No study on the specific distribution of laminin and type IV collagen chain isoforms has been reported.…”

Section: Introductionmentioning

confidence: 99%

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Glomerular extracellular matrix and growth factors in diffuse mesangial sclerosis

Yang¹,

Zhang²,

Sich³

et al. 2001

Pediatric Nephrology

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(1) to analyze the glomerular distribution of extracellular matrix (ECM) antigens at the early stage of DMS, (2) to determine the composition of the ECM accumulated within the mesangial areas and leading to glomerular sclerosis, and (3) to analyze the expression of growth factors, transforming growth factor-beta 1 (TGF beta 1) and platelet-derived growth factor A (PDGFA). In glomeruli of patients with IDMS and DDS, the glomerular basement membrane (GBM) expression of the heparan sulfate chain of heparan sulfate proteoglycan (HSPG) was decreased from the early stage of DMS, at a time when ECM proteins retained a normal distribution. In fully developed lesions, mesangial and subendothelial accumulation of collagenous and noncollagenous glycoproteins normally expressed in the mesangial area (types IV [alpha 1(IV)2 alpha 2(IV)] and VI collagen, beta 1 laminin, fibronectin, tenascin, and perlecan) increased with progression of mesangial sclerosis. This was associated with mesangial expression of proteins normally restricted to the GBM (agrin, alpha 1/alpha 5, beta 2, and gamma 1 laminin chains) and with accumulation of chondroitin sulfate proteoglycan. The distribution of the alpha 3-alpha 5 chains of type IV collagen was normal. Focal accumulation of types I, III, and V collagen was seen only in severely sclerotic glomeruli. Expression of growth factors TGF beta 1 and PDGFA was increased in 9 of 10 and 5 of 10 patients, respectively. Early decreased GBM expression of the heparan sulfate chain of HSPG could play a role in the proteinuria of DMS patients. Changes in the composition of the ECM accumulated within the mesangial areas are not specific. We speculate that deregulation of the expression of growth factors normally downregulated by WT1, is one of the factors responsible for the rapid and massive mesangial deposition of basement membrane material in DDS.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 81%

Section: Introductionmentioning

confidence: 99%

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Glomerular extracellular matrix and growth factors in diffuse mesangial sclerosis

Yang¹,

Zhang²,

Sich³

et al. 2001

Pediatric Nephrology

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“…In the kidney, this antibody predominantly stained the GBM in a linear manner. Similar results were obtained with other monoclonal and polyctonal antibodies raised against GBM-HSPG, and with a mAb that recognizes an epitope on the HS chain [5,8,91. The homogenous distribution of this HSPG within the GBM was confirmed by immunoelectron microscopy.…”

Section: Discussionsupporting

confidence: 84%

Evidence for the Existence of Multiple Heparan Sulfate Proteoglycans in the Human Glomerular Basement Membrane and Mesangial Matrix

Groffen

Hop

Tryggvason

et al. 1997

European Journal of Biochemistry

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Heparan sulfate proteoglycans (HSPGs) are essential components of the glomerular basement membrane (GBM) carrying a strong anionic charge. A well-characterized extracellular HSPG is perlecan, ubiquitously expressed in basement membranes. A cDNA construct encoding domains I and I1 of human perlecan was expressed as a fusion protein with glutathione S-transferase. This fusion protein was used to generate monoclonal antibody 95J10. We compared the staining pattern of 95J10 with that of M215, a previously prepared mAb that recognizes HSPG isolated from human GBM. In kidney cortex, the antiperlecan mAb 95J10 showed a strong staining of the mesangium, Bowman's capsule, the tubular basement membrane, and stained the GBM only slightly. In contrast, M215 predominantly stained the GBM in a linear fashion. Immunoelectron microscopy supported these results, showing concentrations of perlecan in some regions of the GBM, whereas the unidentified M215 antigen was homogenously distributed throughout the GBM. In other human tissues, both antibodies also produced a different staining pattern. Furthermore, a polyclonal antiserum recognizing HSPG isolated from the GBM did not recognize perlecan from EHS tumors. These results provide evidence for the presence of another HSPG in the GBM that is immunologically distinct from perlecan. The absence of perlecan splice variants in the kidney suggests that this component is encoded by a different gene than perlecan. Given its marked expression in the GBM, this component could be a determining factor in the maintenance of selective glomerular permeability.Keywords: perlecan; heparan sulfate proteoglycan ; prokaryotic expression; glomerular basement membrane.The glomerular basement membrane (GBM) is a specialized extracellular matrix located at the interface of the glomerular visceral epithelium and the vascular endothelium. The GBM provides a rigid structure that supports the tissue to withstand high local blood pressure, its mechanical strength being enhanced by the highly organized interplay of its biopolymer components [e.g. collagen IV, laminin, nidogen, and heparan sulfate proteoglycan (HSPGs)] [l]. Another crucial function of the GBM is to regulate the passage of proteins depending on their molecular size and charge [2]. The impermeability of the GBM for anionic macromolecules is assigned to the presence of HSPGs anchored within it. The electrostatic charge of these HSPGs can be visualized by electron microscopy using cationic ferritin [2] or heparan sulfate (HS)-specific mAbs [3]. The significance of this mechanism was demonstrated by perfusing rat

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Hereditary disorders of the glomerular basement membrane

Smeets

Knoers

Heuvel

et al. 1996

Pediatric Nephrology

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Increased knowledge of the biochemical composition of the glomerular basement membrane (GBM) and the introduction of molecular genetics has shed new light on the hereditary disorders of the GBM. In this review three disorders are highlighted. About 85% of the cases reported as Alport syndrome are transmitted as the X-linked form and are due to mutations of the COl4A5 chain localized at Xq22. The autosomal recessive form can be explained by mutations in the COl4A3 and COl4A4 gene. Anti-GBM nephritis leading to loss of the renal allograft in about 1%-5% of transplanted Alport patients can be the tragic consequence of this disorder. Some patients with familial benign hematuria have an abnormality of COl4A4. The nail-patella syndrome is a rare autosomal dominant disorder defined by the association of nail dysplasia, bone abnormalities, and frequently renal disease. The gene is localized in region 9q34.1, COl5A1 is not involved. The Finnish type is the best known of the different forms of congenital nephrotic syndrome. The gene has been mapped to the long arm of chromosome 19. Diffuse mesangial sclerosis occurs in the isolated form and as part of the Denys Drash syndrome. Disturbances of the WT1 function in the epithelial cells can have a role in the renal abnormalities of the Denys Drash syndrome.

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Aberrant proteoglycan composition of the glomerular basement membrane in a patient with Denys-Drash syndrome

Cited by 12 publications

References 0 publications

Glomerular extracellular matrix and growth factors in diffuse mesangial sclerosis

Glomerular extracellular matrix and growth factors in diffuse mesangial sclerosis

Evidence for the Existence of Multiple Heparan Sulfate Proteoglycans in the Human Glomerular Basement Membrane and Mesangial Matrix

Hereditary disorders of the glomerular basement membrane

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