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

Abstract

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.

Keywords: Alternative pathway; Complement; Factor H; Glomerular basement membrane; Heparan sulfate.

Figure 1. Overview of the complement activation cascade

Complement activation is initiated by three pathways (green), converging toward activation of C3, which is further amplified in a positive feed-back loop (blue). The terminal complement pathway (purple) is activated upon the formation of C5 convertases that cleave C5. The underlined components attach covalently to target.

Figure 2. Factor H structure and function

A. Domain organization of factor H and the location of functional sites. B. Factor H inhibits the alternative pathway by several mechanisms: (a) inhibiting the binding of factor B to C3b, (b) accelerating the decay of the C3bBb convertase, and (c) serving as cofactor for factor I (fI), which inactivates C3b to iC3b. The ability of factor H to inhibit complement amplification on self surfaces (depicted as horizontal lines) is contingent upon its recognition of host-specific polyanions, such as heparan sulfate (HS).

Figure 3. GBM heparan sulfate modulates local complement activation

(A.) Heparan sulfate (HS), abundant in the normal GBM, helps recruit factor H to locally inactivate GBM-bound C3b (right). In the absence of GBM heparan sulfate, this regulation is ineffective, allowing local amplification of complement activation (left). (B.) In kidney diseases mediated by glomerular immune complexes, the acquired loss of GBM heparan sulfate chains impairs the recruitment of factor H and the local complement regulation, thereby creating a vicious cycle (shown in red), which amplifies complement activation and exacerbates glomerular injury.