ReviewGlomerular basement membrane heparan sulfate in health and disease: A regulator of local complement activation

- Heparan sulfate chains attached to agrin are abundant in the normal GBM but decreased in various glomerular diseases.
- Studies in mouse models challenge the presumed role of GBM heparan sulfate in the charge selective glomerular filtration.
- Heparan sulfate modulates local complement activation by recruiting complement regulatory proteins from plasma.
- Factor H recognizes heparan sulfate as molecular marker of self to inhibit complement activation on host surfaces.
- The loss of GBM heparan sulfate in glomerular disease is maladaptive, impairing local complement regulation by factor H.

The glomerular basement membrane (GBM) is an essential component of the glomerular filtration barrier. Heparan sulfate proteoglycans such as agrin are major components of the GBM, along with α345(IV) collagen, laminin-521 and nidogen. A loss of GBM heparan sulfate chains is associated with proteinuria in several glomerular diseases and may contribute to the underlying pathology. As the major determinants of the anionic charge of the GBM, heparan sulfate chains have been thought to impart charge selectivity to the glomerular filtration, a view challenged by the negligible albuminuria in mice that lack heparan sulfate in the GBM. Recent studies provide increasing evidence that heparan sulfate chains modulate local complement activation by recruiting complement regulatory protein factor H, the major inhibitor of the alternative pathway in plasma. Factor H selectively inactivates C3b bound to surfaces bearing host-specific polyanions such as heparan sulfate, thus limiting complement activation on self surfaces such as the GBM, which are not protected by cell-bound complement regulators. We discuss mechanisms whereby the acquired loss of GBM heparan sulfate can impair the local regulation of the alternative pathway, exacerbating complement activation and glomerular injury in immune-mediated kidney diseases such as membranous nephropathy and lupus nephritis.