Heparan Sulfate of Perlecan Is Involved in Glomerular Filtration

Morita, Hiroyuki; Yoshimura, Akinobu; Inui, Kentaro; Ideura, Terukuni; Watanabe, Hideto; Wang, Ling; Soininen, Raija; Tryggvason, Karl

doi:10.1681/asn.2004050387

Cited by 89 publications

(82 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…While these recent data suggest that loss of heparan sulphate in the GBM alone does not lead to proteinuria, it is not clear whether loss of heparan sulphate under pathological conditions such as diabetic nephropathy accelerates or worsens proteinuria. An earlier study showed that loss of another heparan sulphate proteoglycan, perlecan, leads to proteinuria in albumin-overloaded perlecandeficient mice [38]. We speculate that loss of heparan sulphate may contribute to the pathogenesis of proteinuria under prolonged hyperglycaemic conditions.…”

Section: Discussionmentioning

confidence: 64%

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

et al. 2007

View full text Add to dashboard Cite

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

show abstract

Section: Discussionmentioning

confidence: 64%

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

et al. 2007

View full text Add to dashboard Cite

show abstract

“…Exon 3 deletion (Hspg2 3/3 ) viable: proteinuria after protein loading (Morita et al 2005); monocyte/macrophage influx impaired in Hspg2 3/3 Col18a1 2/ -mice in a model of renal ischemia/reperfusion (Celie et al 2007). Secreted as CSPG in some tissues (Danielson et al 1992;Govindraj et al 2002;Vogl-Willis and Edwards 2004;West et al 2006), but relationship of CSPG isoform to phenotypes not established.…”

Section: Hspg2mentioning

confidence: 99%

Heparan Sulfate Proteoglycans

Sarrazin¹,

Lamanna²,

Esko

2011

Cold Spring Harbor Perspectives in Biology

1,218

1,238

View full text Add to dashboard Cite

“…15,18 Mice lacking the attachment sites for HS on perlecan have normal glomerular ultrastructure and no renal disease but show increased susceptibility to protein-overload proteinuria. 19,20 Collagen XVIII mutants have mild mesangial expansion and only slightly elevated serum creatinine levels compared with controls. 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.…”

mentioning

confidence: 98%

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

View full text Add to dashboard Cite

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

show abstract

Heparan Sulfate of Perlecan Is Involved in Glomerular Filtration

Abstract: Perlecan is a heparan sulfate proteoglycan and a major component of the glomerular basement membrane. To understand the role of heparan sulfate chains of perlecan in glomerular filtration, detailed analyses were performed of the kidneys of

Cited by 89 publications

References 38 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

Heparan Sulfate Proteoglycans

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

Contact Info

Product

Resources

About