Changes in heparan sulfate correlate with increased glomerular permeability

Abstract

The glomerular capillary wall functions as both a size-selective and charge-selective barrier. Heparan sulfate is known to be an important component of the charge-selective barrier to filtration of polyanions. We studied the alterations in both the charge and size selectivity barriers in a model of experimental membranous nephropathy in the rabbit. The fractional clearance of both charged and uncharged dextrans compared to inulin was measured. Sulfate incorporation into glycosaminoglycans was measured and the glomerular heparan sulfate was isolated and biochemically characterized. Membranous nephropathy in the rabbit was induced with daily injections of cationic bovine serum albumin. After three weeks of injection animals had 735 +/- 196 mg/24 hours of protein excretion. There was no change in [35S] incorporation in 24 hours by experimental animals, 440 +/- 91 DPM/mg dry weight of glomeruli, N = 9 versus 410 +/- 98, N = 11 in controls. The percentage of [35S] incorporated into heparan sulfate versus chondroitin sulfate was decreased, 60% +/- 3 versus 79% +/- 2, P less than 0.001. Heparan sulfate from membranous nephropathy eluted from ion exchange chromatography in a lower molarity salt, indicating a lower effective charge. Fractional clearance of neutral dextrans was significantly increased in membranous nephropathy for dextrans greater than 48 A, while fractional clearance of dextran sulfates was significantly increased compared to controls for dextrans greater than 32 A. Thus, in membranous nephropathy there is loss of both charge selectivity and size selectivity. The loss of charge selectivity correlated with a change in the structure of the glomerular heparan sulfate.(ABSTRACT TRUNCATED AT 250 WORDS)

Basement Membranes: Cell Scaffoldings and Signaling Platforms

“…The polyanionic heparan sulfate chains have been thought to be responsible for the charge-sieving properties of the glomerulus in which acidic macromolecules are preferentially excluded from urine (Groggel et al 1987;Groggel et al 1988). However, recent genetic evidence in which the principal GBM HSPG agrin was selectively knocked out in mouse podocytes revealed that reduction of GBM heparan sulfates did not alter chargeselectivity (Harvey et al 2007).…”

Pattern of Interleukins in Minimal-Change Nephrotic Syndrome of Childhood

“…In most instan ces, renal biopsies do not reveal significant glomerular abnormalities on light microscopy while electron micro scopy reveals changes mainly in glomerular epithelial cells in the form of podocyte fusion. The histochemical staining using cationic dyes like colloidal iron at light-and electronmicroscopic levels had shown reduction in anionic charge sites on the glomerular basement membrane the dominant component of which is heparan sulphate a proteoglycan [1], There is increasing evidence that albuminuria in MCNS is related to a loss of the charge-dependent permselectivity of the glomerular basement membrane in the alteration of the glomerular charge-selective barrier to polyanions [2], Studies on immunological alterations in these children have shown an abnormal immunoglobulin production, a decrease in the number of helper T cells and an increase in the number of suppressor cells with depressed mitogen-in duced blast transformation suggesting impaired cell-medi ated immunity [3][4][5][6]. Though the relationship between im munological alterations and glomerular changes related Accepted : October 20.1992 with proteinuria is not clear, several investigators have suggested that alteration in T cell functions results in the release of certain circulating factors (lymphokines) which modify the glomerular polyanions leading to proteinuria [7], Since the T cell response to lectin-specific antigen in volves a cascade of lymphokine-mediated events which culminate in T cell proliferation and emergence of effector T cells [8,9], we have studied the status of various lympho kines, namely interleukin-1 (IL-1) and IL-2, in these patients to understand their role in the aetiopathogenesis of this disease.…”

Effects of a Low-Protein Diet on Urinary Glycosaminoglycan Excretion in Adriamycin-Treated Rats

“…This evidence comes from observations connecting al terations of glomerular permeability and proteinuria with a loss of anionic sites in different models of experimental glomerulopathies [9][10][11] as well as in the minimal change nephrotic syndrome in man [2,12].…”