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(Received for publication, July 10, 1997, and in revised form, August 6, 1997)
From the Division of Nephrology, University Hospital St.
Radboud, 6500 HB Nijmegen, The Netherlands
Heparan sulfate, the polysaccharide side chain of
heparan sulfate proteoglycan, is important for the permselective
properties of the glomerular basement membrane. In this report, we show
a role for hydroxyl radicals in heparan sulfate degradation and an
enhanced glomerular basement membrane permeability. First, in
enzyme-linked immunosorbent assay, exposure of coated heparan sulfate
(proteoglycan) to reactive oxygen species resulted in a ±50% decrease
of binding of a monoclonal antibody against heparan sulfate, whereas
binding of an antibody against the core protein remained unaltered.
Second, on polyacrylamide gel electrophoresis, the molecular weight of
heparan sulfate exposed to radicals was reduced which indicates
depolymerization. Both in enzyme-linked immunosorbent assay and gel
electrophoresis, hydroxyl radicals are instrumental for heparan sulfate
degradation as shown by the addition of various radical scavengers.
Third, in an experimental model for human nephrotic syndrome
(Adriamycin nephropathy in rats), glomerular basement membrane staining
of two recently described anti-heparan sulfate antibodies (JM403 and
KJ865) was reduced by 24 and 43%. Treatment of Adriamycin-exposed rats
with the hydroxyl radical scavenger dimethylthiourea both reduced
albuminuria by 37% (p < 0.01) and partly prevented
loss of heparan sulfate staining by 53% (JM403) and 39% (KJ865)
(p < 0.03). In contrast to the heparan sulfate side
chains, the core protein expression and the extent of glycanation
did not change in Adriamycin nephropathy. We conclude that glomerular
basement membrane heparan sulfate is susceptible to depolymerization by
hydroxyl radicals leading to loss of glomerular basement membrane
integrity and albuminuria.
Volume 272, Number 42,
Issue of October 17, 1997
pp. 26734-26741
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
Hydroxyl Radicals Depolymerize Glomerular Heparan Sulfate
in Vitro and in Experimental Nephrotic Syndrome
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