title: Neutrophil Extracellular Trap-Related Extracellular Histones Cause Vascular Necrosis in Severe GN.
abstract: Severe GN involves local neutrophil extracellular trap (NET) formation. We hypothesized a local cytotoxic effect of NET-related histone release in necrotizing GN. In vitro, histones from calf thymus or histones released by neutrophils undergoing NETosis killed glomerular endothelial cells, podocytes, and parietal epithelial cells in a dose-dependent manner. Histone-neutralizing agents such as antihistone IgG, activated protein C, or heparin prevented this effect. Histone toxicity on glomeruli ex vivo was Toll-like receptor 2/4 dependent, and lack of TLR2/4 attenuated histone-induced renal thrombotic microangiopathy and glomerular necrosis in mice. Anti-glomerular basement membrane GN involved NET formation and vascular necrosis, whereas blocking NET formation by peptidylarginine inhibition or preemptive anti-histone IgG injection significantly reduced all aspects of GN (i.e., vascular necrosis, podocyte loss, albuminuria, cytokine induction, recruitment or activation of glomerular leukocytes, and glomerular crescent formation). To evaluate histones as a therapeutic target, mice with established GN were treated with three different histone-neutralizing agents. Anti-histone IgG, recombinant activated protein C, and heparin were equally effective in abrogating severe GN, whereas combination therapy had no additive effects. Together, these results indicate that NET-related histone release during GN elicits cytotoxic and immunostimulatory effects. Furthermore, neutralizing extracellular histones is still therapeutic when initiated in established GN.
authors: Division of Nephrology, Department of Internal Medicine IV, Ludwig-Maximilians-University of Munich, Munich, Germany;
authors: Santhosh V R
authors: SV
authors: Kumar
authors: Division of Nephrology, Department of Internal Medicine IV, Ludwig-Maximilians-University of Munich, Munich, Germany;
authors: Onkar P
authors: OP
authors: Kulkarni
authors: Division of Nephrology, Department of Internal Medicine IV, Ludwig-Maximilians-University of Munich, Munich, Germany;
authors: Shrikant R
authors: SR
authors: Mulay
authors: Division of Nephrology, Department of Internal Medicine IV, Ludwig-Maximilians-University of Munich, Munich, Germany;
authors: Murthy N
authors: MN
authors: Darisipudi
authors: Division of Nephrology, Department of Internal Medicine IV, Ludwig-Maximilians-University of Munich, Munich, Germany;
authors: Simone
authors: S
authors: Romoli
authors: Division of Nephrology, Department of Internal Medicine IV, Ludwig-Maximilians-University of Munich, Munich, Germany;
authors: Dana
authors: D
authors: Thomasova
authors: Division of Nephrology, Department of Internal Medicine IV, Ludwig-Maximilians-University of Munich, Munich, Germany;
authors: Christina R
authors: CR
authors: Scherbaum
authors: Division of Nephrology, Department of Internal Medicine III, Dresden University of Technology, Dresden, Germany;
authors: Bernd
authors: B
authors: Hohenstein
authors: Division of Nephrology, Department of Internal Medicine III, Dresden University of Technology, Dresden, Germany;
authors: Christian
authors: C
authors: Hugo
authors: Institute of Pathology, University of Munich, Munich, Germany; and.
authors: Susanna
authors: S
authors: Müller
authors: Department of Pathology and Immunology, School of Medicine, Washington University in Saint Louis, Saint Louis, Missouri.
authors: Helen
authors: H
authors: Liapis
authors: Division of Nephrology, Department of Internal Medicine IV, Ludwig-Maximilians-University of Munich, Munich, Germany; hjanders@med.uni-muenchen.de.
authors: Hans-Joachim
authors: HJ
authors: Anders
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000473:pathology*; D002417:Cattle; D065206:Extracellular Traps / Q000187:drug effects / Q000502:physiology*; D005921:Glomerulonephritis / Q000150:complications* / Q000188:drug therapy / Q000209:etiology; D006657:Histones / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D009336:Necrosis / Q000209:etiology; D012720:Severity of Illness Index
chemical_list: D006657:Histones
keywords: ARF; glomerular endothelial cells; immunology; pathology
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