title: Histones and Neutrophil Extracellular Traps Enhance Tubular Necrosis and Remote Organ Injury in Ischemic AKI.
abstract: Severe AKI is often associated with multiorgan dysfunction, but the mechanisms of this remote tissue injury are unknown. We hypothesized that renal necroinflammation releases cytotoxic molecules that may cause remote organ damage. In hypoxia-induced tubular epithelial cell necrosisin vitro, histone secretion from ischemic tubular cells primed neutrophils to form neutrophil extracellular traps. These traps induced tubular epithelial cell death and stimulated neutrophil extracellular trap formation in fresh neutrophils.In vivo, ischemia-reperfusion injury in the mouse kidney induced tubular necrosis, which preceded the expansion of localized and circulating neutrophil extracellular traps and the increased expression of inflammatory and injury-related genes. Pretreatment with inhibitors of neutrophil extracellular trap formation reduced kidney injury. Dual inhibition of neutrophil trap formation and tubular cell necrosis had an additive protective effect. Moreover, pretreatment with antihistone IgG suppressed ischemia-induced neutrophil extracellular trap formation and renal injury. Renal ischemic injury also increased the levels of circulating histones, and we detected neutrophil infiltration and TUNEL-positive cells in the lungs, liver, brain, and heart along with neutrophil extracellular trap accumulation in the lungs. Inhibition of neutrophil extracellular trap formation or of circulating histones reduced these effects as well. These data suggest that tubular necrosis and neutrophil extracellular trap formation accelerate kidney damage and remote organ dysfunction through cytokine and histone release and identify novel molecular targets to limit renal necroinflammation and multiorgan failure.
authors.affiliation: Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany.
authors.forename: Daigo
authors.initials: D
authors.lastname: Nakazawa
authors.affiliation: Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany.
authors.forename: Santhosh V
authors.initials: SV
authors.lastname: Kumar
authors.affiliation: Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany.
authors.forename: Julian
authors.initials: J
authors.lastname: Marschner
authors.affiliation: Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany.
authors.forename: Jyaysi
authors.initials: J
authors.lastname: Desai
authors.affiliation: Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Holderied
authors.affiliation: Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany.
authors.forename: Lukas
authors.initials: L
authors.lastname: Rath
authors.affiliation: Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Kraft
authors.affiliation: Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany.
authors.forename: Yutian
authors.initials: Y
authors.lastname: Lei
authors.affiliation: Department of Pathology, Sapporo City General Hospital, Sapporo, Hokkaido, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Fukasawa
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Gilbert W
authors.initials: GW
authors.lastname: Moeckel
authors.affiliation: Excellence Centre for Research, Transfer and High Education for the Development of De Novo Therapies, University of Florence, Florence, Italy; and.
authors.forename: Maria Lucia
authors.initials: ML
authors.lastname: Angelotti
authors.affiliation: Departments of Pathology and Immunology and Internal Medicine (Renal), School of Medicine, Washington University in St. Louis, Missouri and Arkana Laboratories, Little Rock, Arkansas.
authors.forename: Helen
authors.initials: H
authors.lastname: Liapis
authors.affiliation: Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany; hjanders@med.uni-muenchen.de.
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Anders
mesh_terms: D058186:Acute Kidney Injury / Q000150:complications*; D000818:Animals; D002478:Cells, Cultured; D065206:Extracellular Traps / Q000502:physiology*; D006657:Histones / Q000502:physiology; D006801:Humans; D007511:Ischemia / Q000150:complications*; D007668:Kidney / Q000098:blood supply*; D007673:Kidney Cortex Necrosis / Q000209:etiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils; D012720:Severity of Illness Index
chemical_list: D006657:Histones
keywords: AKI related remote organ injury; Ischemic reperfusion injury; NETs; necroinflammation; tubular cell death