A monoclonal antibody against GBM heparan sulfate induces an acute selective proteinuria in rats

Born, Jacob van den; Heuvel, Lambertus P. van den; Bakker, Marinka A.H.; Veerkamp, J.H.; Assmann, K.J.M.; Berden, Jo H. M.

doi:10.1038/ki.1992.15

Cited by 215 publications

(103 citation statements)

References 33 publications

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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: 74%

“…A similar effect was observed when the kidney was perfused with anti-HS mAbs [5]. Alterations in the HS content of the GBM causing nephrotic syndrome are involved in, for example, minimal change nephropathy, glomerulonephritis, diabetes mellitus, and Denys-Drash syndrome [6 -8 1. For biochemical characterization, HSPGs were extracted from isolated glomeruli [9], from epithelial cell lines [lo], or from the mouse Engelbreth-Holm-Swarm sarcoma [I 1 -13].…”

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confidence: 71%

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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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Section: Discussionsupporting

confidence: 74%

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confidence: 71%

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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“…For example, rats developed massive albuminuria after injection of the mAb JM403 [6]. Degradation of heparan sulphate by the bacterial heparan sulphate-cleaving enzyme heparinase III resulted in an increased permeability of the GBM to ferritin and albumin [2][3][4].…”

Section: Discussionmentioning

confidence: 99%

“…Neutralisation of GBM anionic charges after perfusion of isolated rat kidneys or infusion of the renal artery with the cationic probe protamine also resulted in increased permeability of the GBM to albumin [4,5]. In addition, binding to GBM heparan sulphate after intravenous injection of rats with the monoclonal anti-heparan sulphate antibody JM403 induced acute selective proteinuria [6].…”

Section: Introductionmentioning

confidence: 99%

Heparanase induces a differential loss of heparan sulphate domains in overt diabetic nephropathy

et al. 2007

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Aims/hypothesis Recent studies suggest that loss of heparan sulphate in the glomerular basement membrane (GBM) of the kidney with diabetic nephropathy is due to the increased production of heparanase, a heparan sulphate-degrading endoglycosidase. Our present study addresses whether heparan sulphate with different modifications is differentially reduced in the GBM and whether heparanase selectively cleaves heparan sulphate with different domain specificities. Methods The heparan sulphate content of renal biopsies (14 diabetic nephropathy, five normal) were analysed by immunofluorescence staining with four anti-heparan sulphate antibodies: JM403, a monoclonal antibody (mAb) recognising N-unsubstituted glucosamine residues; two phage displayderived single chain antibodies HS4C3 and EW3D10, defining sulphated heparan sulphate domains; and anti-K5 antibody, an mAb recognising unmodified heparan sulphate domains. Results We found that modified heparan sulphate domains (JM403, HS4C3 and EW3D10), but not unmodified domains (anti-K5) and agrin core protein were reduced in the GBM of kidneys from patients with diabetic nephropathy, compared with controls. Glomerular heparanase levels were increased in diabetic nephropathy kidneys and inversely correlated with the amounts of modified heparan sulphate domains. Increased heparanase production and loss of JM403 staining in the GBM Diabetologia (2008) 51:372-382

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“…First, digestion of HS by heparitinase resulted in increased permeability of the GBM for ferritin and albumin (2,3). Second, injection of a specific mAb against HS caused massive albuminuria in rats (4). Third, loss of anionic HS has been reported in several human and experimental glomerulopathies, which was inversely correlated with the degree of proteinuria (5,6).…”

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Induction of Glomerular Heparanase Expression in Rats with Adriamycin Nephropathy Is Regulated by Reactive Oxygen Species and the Renin-Angiotensin System

Kramer¹,

Hoven²,

Rops³

et al. 2006

Journal of the American Society of Nephrology

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Heparan sulfate (HS) in the glomerular basement membrane (GBM) is important for regulation of the charge-dependent permeability. Heparanase has been implicated in HS degradation in several proteinuric diseases. This study analyzed the role of heparanase in HS degradation in Adriamycin nephropathy (AN), a model of chronic proteinuria-induced renal damage. Expression of heparanase, HS, and the core protein of agrin (to which HS is attached) was determined on kidney sections from rats with AN in different experiments. First, expression was examined in a model of unilateral AN in a time-course study at 6-wk intervals until week 30. Second, rats were treated with the hydroxyl radical scavenger dimethylthiourea (DMTU) during bilateral AN induction. Finally, 6 wk after AN induction, rats were treated with angiotensin II receptor type 1 antagonist (AT1A) or vehicle for 2 wk. Heparanase expression was increased in glomeruli of rats with AN, which correlated with HS reduction at all time points and in all experiments. Treatment with DMTU prevented the increased heparanase expression, the loss of GBM HS, and reduced albuminuria. Finally, treatment of established proteinuria with AT1A significantly reduced heparanase expression and restored glomerular HS. In conclusion, an association between heparanase expression and reduction of glomerular HS in AN was observed. The effects of DMTU suggest a role for reactive oxygen species in upregulation of heparanase. Antiproteinuric treatment by AT1A decreased heparanase expression and restored HS expression. These results suggest involvement of radicals and angiotensin II in the modulation of GBM permeability through HS and heparanase expression.

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A monoclonal antibody against GBM heparan sulfate induces an acute selective proteinuria in rats

Cited by 215 publications

References 33 publications

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

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

Heparanase induces a differential loss of heparan sulphate domains in overt diabetic nephropathy

Induction of Glomerular Heparanase Expression in Rats with Adriamycin Nephropathy Is Regulated by Reactive Oxygen Species and the Renin-Angiotensin System

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