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

Matrix Biol. 2017 Jan;57-58:299-310. doi: 10.1016/j.matbio.2016.09.002. Epub 2016 Sep 6.

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.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Agrin / genetics
  • Agrin / immunology
  • Animals
  • Collagen Type IV / genetics
  • Collagen Type IV / immunology
  • Complement Activation*
  • Complement C3b / genetics
  • Complement C3b / metabolism
  • Complement Factor H / genetics
  • Complement Factor H / metabolism
  • Gene Expression Regulation / immunology*
  • Glomerular Basement Membrane / immunology*
  • Glomerular Basement Membrane / metabolism
  • Glomerulonephritis, Membranous / genetics
  • Glomerulonephritis, Membranous / immunology*
  • Glomerulonephritis, Membranous / pathology
  • Heparitin Sulfate / immunology*
  • Heparitin Sulfate / metabolism
  • Humans
  • Laminin / genetics
  • Laminin / immunology
  • Lupus Nephritis / genetics
  • Lupus Nephritis / immunology*
  • Lupus Nephritis / pathology
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / immunology
  • Signal Transduction
  • Static Electricity

Substances

  • Agrin
  • Collagen Type IV
  • Laminin
  • Membrane Glycoproteins
  • laminin 11 protein, human
  • nidogen
  • Complement C3b
  • Complement Factor H
  • Heparitin Sulfate