Reduction in glomerular heparan sulfate correlates with complement deposition and albuminuria in active heymann nephritis

In a time-study of active Heymann nephritis, the expression of agrin, the m ain heparan sulfate proteoglycan in the glomerular basement membrane, was a nalyzed in relation to deposition of IgG and complement in the glomerular c apillary wall and the development of albuminuria. Binding of IgG autoantibo dies to the glomerular capillary wall could be detected from 2, wk onward, followed by activation of complement after 6 wk. progressive albuminuria de veloped from 6 wk onward to a level of 274 +/- 68 mg/18 h at week 12. The s taining intensity for the agrin core protein decreased slightly, and the st aining intensity for the heparan sulfate stubs that were still attached to the core protein after heparitinase digestion remained normal. From week 6 onward, however, a progressive decrease was seen in the staining of two mon oclonal antibodies (mAb) directed against different epitopes on the heparan sulfate polysaccharide side chain of agrin (to 35 and 30% of the control l evel, respectively, at week 12, both mAb P = 0.016). Moreover, albuminuria was inversely correlated with heparan sulfate staining as revealed by these antibodies (r(s) = -0.82 and r(s) = -0.75, respectively, both mAb P < 0.00 01). This decrease in heparan sulfate staining was due to a progressive red uction of glomerular heparan sulfate content to 46 and 32% of control level at week 10 and week 12 of the disease, respectively, as measured biochemic ally. It is speculated that the observed decrease in glomerular heparan sul fate in active Heymann nephritis is due to complement-mediated cleavage of heparan sulfate, resulting in an increased permeability of the glomerular b asement membrane to macromolecules.