title: Heparin exerts a dual effect on murine lupus nephritis by enhancing enzymatic chromatin degradation and preventing chromatin binding in glomerular membranes.
abstract: OBJECTIVE
  Association of nucleosome-IgG immune complexes with glomerular basement membranes (GBMs) is an important event in the development of lupus nephritis. Preventing this binding and/or increasing nuclease sensitivity of nucleosomes may be viable strategies for the prevention of the disease. Theoretically, heparin may alter nucleosomal structure and increase sensitivity to proteinases and nucleases, and may also inhibit binding of nucleosomes and nucleosome-IgG complexes to basement membrane structures. The aim of this study was to investigate whether and eventually how heparin prevents murine lupus nephritis.
  
  
  METHODS
  Surface plasmon resonance was used to analyze if heparin inhibits binding of nucleosomes to laminin and collagen. The effect of heparin on nuclease- and proteinase-mediated degradation of nucleosomes was analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and agarose gel electrophoresis. In vitro results were compared with analyses in vivo in heparin-treated (NZB × NZW)F(1) mice. Anti-double-stranded DNA antibody production, deposition of nucleosome-IgG complexes in GBMs, and development of proteinuria were monitored, and circulating chromatin fragments were quantified using quantitative polymerase chain reaction.
  
  
  RESULTS
  In vitro studies demonstrated that heparin increased enzymatic degradation of nucleosomes and almost completely inhibited binding of nucleosomes to laminin and collagen. (NZB × NZW)F(1) mice treated with heparin demonstrated delayed or no antibody production and higher variation of circulating chromatin levels compared with untreated control mice. This effect was accompanied by highly reduced nucleosome-IgG complexes in GBMs and delayed development of nephritis.
  
  
  CONCLUSIONS
  Increasing the degradation of nucleosomes, reducing their immunogenicity, and preventing binding of nucleosome-IgG complexes in glomeruli together provide an alternative basis for the treatment of lupus nephritis.
authors.affiliation: University of Tromsø, Tromsø, Norway.
authors.forename: Annica
authors.initials: A
authors.lastname: Hedberg
authors.forename: Silje
authors.initials: S
authors.lastname: Fismen
authors.forename: Kristin A
authors.initials: KA
authors.lastname: Fenton
authors.forename: Chris
authors.initials: C
authors.lastname: Fenton
authors.forename: Bjarne
authors.initials: B
authors.lastname: Osterud
authors.forename: Elin S
authors.initials: ES
authors.lastname: Mortensen
authors.forename: Ole Petter
authors.initials: OP
authors.lastname: Rekvig
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002462:Cell Membrane / Q000378:metabolism* / Q000473:pathology; D002843:Chromatin / Q000187:drug effects* / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005343:Fibrinolytic Agents / Q000494:pharmacology / Q000627:therapeutic use; D006493:Heparin / Q000494:pharmacology* / Q000627:therapeutic use; D007074:Immunoglobulin G / Q000378:metabolism; D007678:Kidney Glomerulus / Q000378:metabolism* / Q000473:pathology; D007797:Laminin / Q000378:metabolism; D008181:Lupus Nephritis / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008814:Mice, Inbred NZB; D009707:Nucleosomes / Q000187:drug effects / Q000378:metabolism
chemical_list: D002843:Chromatin; D005343:Fibrinolytic Agents; D007074:Immunoglobulin G; D007797:Laminin; D009707:Nucleosomes; D006493:Heparin; D003094:Collagen