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 nucleaseand 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-doublestranded 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 nucleosomeIgG complexes in GBMs and delayed development of nephritis.Conclusion. 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.

Low molecular weight heparin tinzaparin antagonizes cisplatin resistance of ovarian cancer cells

“…It is known that heparin can interact with chromatin and nucleosomes and may thus affect gene expression 44,45 . However, we can rule out intracellular activities of tinzaparin, because we did not detect any uptake of LMWH in A2780cis cells, and former data on heparin chromatin interactions have been derived from cell lysates and not from living cells 44,45 .…”

Circulating levels of chromatin fragments are inversely correlated with anti-dsDNA antibody levels in human and murine systemic lupus erythematosus

“…This hypothesis has its origin in a recent longitudinal study of progressive lupus nephritis in B/W mice [13]. We have recently published data on the effect of heparin treatment leading to enhanced nucleosome degradation and reduced chromatin deposition within the MM and the GBM of glomeruli of (NZBXNZW)F1 mice [52]. Heparin binds to chromatin and makes it more susceptible for degradation by both proteases and nucleases.…”

Heparin calcium treated Henoch–Schönlein purpura nephritis in children through inhibiting hyperfibrinolysis

“…It could delay the development of HSPN through effectively inhibiting the hyperplasia of glomerular mesangial cells and renal matrix. While exploring how the heparin impeded murine lupus nephritis in mice, Hedberg et al 23 discovered that heparin increased enzymatic degradation of nucleosomes and almost completely inhibited binding of nucleosomes to laminin and collagen, after heparin therapy, the nucleosomes-IgG compound on the murine glomerular basement membrane reduced significantly and the development of nephritis was delayed.…”