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.

Isotopic Nitrogen-15 Labeling of Mice Identified Long-lived Proteins of the Renal Basement Membranes

“…By contrast, agrin had only 4.7% remaining 14 N in both fractions (Fig. 3C), consistent with its association with the lamina rara that is constantly renewed by the podocytes and endothelia 23,25,26 .…”

Extracellular Matrix in Kidney Fibrosis: More Than Just a Scaffold

“…75 In total, 16 different combinations of these chains have been identified in mammals, for example, laminin α1β1γ1. 76 Laminins are a major constituent of the GBM, 77 mesangial ECM 58 and tubular basement membranes. 78 Similar to the change in the collagen IV network, there is a shift in laminin isoform expression during renal development in the GBM.…”

Endothelial glycocalyx restoration by growth factors in diabetic nephropathy

“…Here it is primarily found as part of the proteoglycan, agrin [59,60]. Whether GBM HS plays a role in protein restriction is under debate [59,[61][62][63], although a general note for these and all Glx studies is that there is a need to discriminate between GAG of eGlx and elsewhere (i.e GBM, podocytes and mesangial cells).…”