Changes in heparan sulfate correlate with increased glomerular permeability

Changes in heparan sulfate correlate with increased glomerular permeability. 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 < 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 Å, while fractional clearance of dextran sulfates was significantly increased compared to controls for dextrans greater than 32 Å. 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. The change in structure of the heparan sulfate could be the initiating event in the altered glomerular permeability of experimental membranous nephropathy