Neutrophil Extracellular Trap-Related Extracellular Histones Cause Vascular Necrosis in Severe GN

作者: Santhosh V.R. Kumar , Onkar P. Kulkarni , Shrikant R. Mulay , Murthy N. Darisipudi , Simone Romoli

DOI: 10.1681/ASN.2014070673

关键词:

摘要: Severe GN involves local neutrophil extracellular trap (NET) formation. We hypothesized a cytotoxic effect of NET-related histone release in necrotizing GN. In vitro, histones from calf thymus or released by neutrophils undergoing NETosis killed glomerular endothelial cells, podocytes, and parietal epithelial cells dose-dependent manner. Histone-neutralizing agents such as antihistone IgG, activated protein C, heparin prevented this effect. Histone toxicity on glomeruli ex vivo was Toll-like receptor 2/4 dependent, lack TLR2/4 attenuated histone-induced renal thrombotic microangiopathy necrosis mice. Anti-glomerular basement membrane involved NET formation vascular necrosis, whereas blocking peptidylarginine inhibition preemptive anti-histone IgG injection significantly reduced all aspects (i.e., podocyte loss, albuminuria, cytokine induction, recruitment activation leukocytes, crescent formation). To evaluate therapeutic target, mice with established were treated three different histone-neutralizing agents. Anti-histone recombinant equally effective abrogating severe GN, combination therapy had no additive effects. Together, these results indicate that during elicits immunostimulatory Furthermore, neutralizing is still when initiated

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