Agrin Is a Major Heparan Sulfate Proteoglycan in the Human Glomerular Basement Membrane

Groffen, Alexander J.; Rüegg, Markus A.; Dijkman, H.B.P.M.; Velden, T.J. van de; Buskens, C.A.F.; Born, Jacob van den; Assmann, K.J.M.; Monnens, L.A.H.; Veerkamp, J.H.; Heuvel, Lambert P. van den

doi:10.1177/002215549804600104

Cited by 155 publications

(111 citation statements)

References 40 publications

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“…1c). These results indicate that the decreased staining of the GBM by antiheparan sulphate antibody JM403 is not due to reduced synthesis of the core protein of agrin, which is the major heparan sulphate proteoglycan in the GBM [24,25]. In this analysis we also observed an inverse correlation between the heparan sulphate domain content of the GBM and the level of proteinuria (Fig.…”

Section: Resultssupporting

confidence: 66%

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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Section: Resultssupporting

confidence: 66%

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

et al. 2007

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“…54 Furthermore, agrin is a major heparan sulfate proteoglycan in the adult GBM. 17,55 The anionic heparan sulfate side chains of agrin play an important role in the maintenance of the charge-dependent permeability of the GBM. 56 -58 In the present study, we observed a difference in ultrastructural localization between the N-and C-terminus of agrin.…”

Section: Discussionmentioning

confidence: 99%

Expression of Agrin, Dystroglycan, and Utrophin in Normal Renal Tissue and in Experimental Glomerulopathies

Raats

Born

Bakker

et al. 2000

The American Journal of Pathology

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The dystrophin-glycoprotein complex, which comprises ␣-and ␤-dystroglycan, sarcoglycans, and utrophin/dystrophin, links the cytoskeleton to agrin and laminin in the basal lamina in muscle and epithelial cells. Recently, agrin was identified as a major heparan sulfate proteoglycan in the glomerular basement membrane. In the present study, we found mRNA expression for agrin, dystroglycan, and utrophin in kidney cortex, isolated glomeruli, and cultured podocytes and mesangial cells. In immunofluorescence, agrin was found in the glomerular basement membrane. The antibodies against ␣-and ␤-dystroglycan and utrophin revealed a granular podocyte-like staining pattern along the glomerular capillary wall. With immunoelectron microscopy, agrin was found in the glomerular basement membrane, dystroglycan was diffusely found over the entire cell surface of the podocytes, and utrophin was localized in the cytoplasm of the podocyte foot processes. In adriamycin nephropathy, a decrease in the glomerular capillary wall staining for dystroglycan was observed probably secondary to the extensive fusion of foot processes. Immunoelectron microscopy showed a different distribution pattern as compared to the normal kidney, with segmentally enhanced expression of dystroglycan at the basal side of the extensively fused podocyte foot processes. In passive Heymann nephritis we observed no changes in the staining intensity and distribution of the dystrophin-glycoprotein complex by immunofluorescence and immunoelectron microscopy. From these data, we conclude that agrin, dystroglycan, and utrophin are present in the glomerular capillary wall and their ultrastructural localization supports the concept that these molecules are involved in linking the podocyte cytoskeleton to the glomerular basement membrane. (Am J Pathol 2000, 156:1749 -1765) Dystroglycan (DG) is an important member of the dystrophin-glycoprotein complex (DGC) which links the subsarcolemmal cytoskeleton to the basal lamina in skeletal muscle.1 The importance of this link becomes clear from the severe muscular dystrophies resulting from mutations in genes that encode different members of the DGC. 2-5

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“…22,23,40 In contrast, N-terminal antibodies label glomerular, tubular, and vascular smooth muscle BMs uniformly. 40 The reason for this discrepancy is unknown, but it might reflect alternative splicing or processing of agrin.…”

Section: Agrn Knockout Mice Synthesize N-terminal Truncated Forms Of mentioning

confidence: 96%

“…21 Agrin has been identified as the predominant GBM-HSPG in all species studied, prompting speculation that it may be a critical determinant of the charge barrier. 22,23 It is characterized by an ϳ2000-residue core protein of ϳ220 kd that carries at least two GAG chains, bringing its mass to ϳ400 kd. Agrin is generally classified as an HSPG, but it can carry both heparan and chondroitin sulfate (CS) GAGs.…”

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confidence: 99%

Disruption of Glomerular Basement Membrane Charge through Podocyte-Specific Mutation of Agrin Does Not Alter Glomerular Permselectivity

Harvey

Jarad

Cunningham

et al. 2007

The American Journal of Pathology

156

127

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Glomerular charge selectivity has been attributed to anionic heparan sulfate proteoglycans (HSPGs) in the glomerular basement membrane (GBM). Agrin is the predominant GBM-HSPG, but evidence that it contributes to the charge barrier is lacking, because newborn agrin-deficient mice die from neuromuscular defects. To study agrin in adult kidney, a new conditional allele was used to generate podocyte-specific knockouts. Mutants were viable and displayed no renal histopathology up to 9 months of age. Perlecan, a HSPG normally confined to the mesangium in mature glomeruli, did not appear in the mutant GBM, which lacked heparan sulfate. Moreover, GBM agrin was found to be derived primarily from podocytes. Polyethyleneimine labeling of fetal kidneys revealed anionic sites along both laminae rarae of the GBM that became most prominent along the subepithelial aspect at maturity; labeling was greatly reduced along the subepithelial aspect in agrin-deficient and conditional knockout mice. Despite this severe charge disruption, the glomerular filtration barrier was not compromised, even when challenged with bovine serum albumin overload. We conclude that agrin is not required for establishment or maintenance of GBM architecture. Although agrin contributes significantly to the anionic charge to the GBM, both it and its charge are not needed for glomerular permselectivity. This calls into question whether charge selectivity is a

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Agrin Is a Major Heparan Sulfate Proteoglycan in the Human Glomerular Basement Membrane

Cited by 155 publications

References 40 publications

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

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

Expression of Agrin, Dystroglycan, and Utrophin in Normal Renal Tissue and in Experimental Glomerulopathies

Disruption of Glomerular Basement Membrane Charge through Podocyte-Specific Mutation of Agrin Does Not Alter Glomerular Permselectivity

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