Reduction in Glomerular Heparan Sulfate Correlates with Complement Deposition and Albuminuria in Active Heymann Nephritis

Abstract

Abstract. In a time-study of active Heymann nephritis, the expression of agrin, the main heparan sulfate proteoglycan in the glomerular basement membrane, was analyzed in relation to deposition of IgG and complement in the glomerular capillary wall and the development of albuminuria. Binding of IgG autoantibodies to the glomerular capillary wall could be detected from 2 wk onward, followed by activation of complement after 6 wk. Progressive albuminuria developed from 6 wk onward to a level of 274 ± 68 mg/18 h at week 12. The staining intensity for the agrin core protein decreased slightly, and the staining 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 monoclonal antibodies (mAb) directed against different epitopes on the heparan sulfate polysaccharide side chain of agrin (to 35 and 30% of the control level, respectively, at week 12, both mAb P = 0.016). Moreover, albuminuria was inversely correlated with heparan sulfate staining as revealed by these antibodies (rs = -0.82 and rs = -0.75, respectively, both mAb P < 0.0001). This decrease in heparan sulfate staining was due to a progressive reduction of glomerular heparan sulfate content to 46 and 32% of control level at week 10 and week 12 of the disease, respectively, as measured biochemically. It is speculated that the observed decrease in glomerular heparan sulfate in active Heymann nephritis is due to complement-mediated cleavage of heparan sulfate, resulting in an increased permeability of the glomerular basement membrane to macromolecules.

Kidney diseases

“…187 In MN, alternative pathway activation may also occur independently of immune complexes, due to local complement dysregulation. In particular, the loss of heparan sulfate chains from the glomerular basal membrane, which has been observed in human and experimental MN, 183,188,189 could lead to impaired recruitment of factor H, the major inhibitor of the AP in plasma. It has also been posited that FHAA, which have been reported in a small subset of patients with primary MN, 190,191 may contribute to the activation of the AP.…”

The role of the complement system in primary membranous nephropathy: A narrative review in the era of new therapeutic targets

“…Heparan sulphate chains in the glomerular basement membrane normally recruit plasma factor H to regulate the local alternative pathway of complement. Expression of heparanases leading to loss of glomerular heparan sulphate has been associated with complement deposition and proteinuria in Heymann nephritis ( 72 ). Several reports further suggested that anti-complement factor H (anti-CFH) antibodies may be expressed in MN, although the evidence is conflicting.…”