Endothelial NF- κ B Blockade Abrogates ANCA-Induced GN

J Am Soc Nephrol. 2017 Nov;28(11):3191-3204. doi: 10.1681/ASN.2016060690. Epub 2017 Jul 7.


ANCA-associated vasculitis (AAV) is a highly inflammatory condition in which ANCA-activated neutrophils interact with the endothelium, resulting in necrotizing vasculitis. We tested the hypothesis that endothelial NF-κB mediates necrotizing crescentic GN (NCGN) and provides a specific treatment target. Reanalysis of kidneys from previously examined murine NCGN disease models revealed NF-κB activation in affected kidneys, mostly as a p50/p65 heterodimer, and increased renal expression of NF-κB-dependent tumor necrosis factor α (TNF-α). NF-κB activation positively correlated with crescent formation, and nuclear phospho-p65 staining showed NF-κB activation within CD31-expressing endothelial cells (ECs) in affected glomeruli. Therefore, we studied the effect of ANCA on NF-κB activation in neutrophil/EC cocultures in vitro ANCA did not activate NF-κB in primed human neutrophils, but ANCA-stimulated primed neutrophils activated NF-κB in ECs, at least in part via TNF-α release. This effect increased endothelial gene transcription and protein production of NF-κB-regulated interleukin-8. Moreover, upregulation of endothelial NF-κB promoted neutrophil adhesion to EC monolayers, an effect that was inhibited by a specific IKKβ inhibitor. In a murine NCGN model, prophylactic application of E-selectin-targeted immunoliposomes packed with p65 siRNA to downregulate endothelial NF-κB significantly reduced urine abnormalities, renal myeloid cell influx, and NCGN. Increased glomerular endothelial phospho-p65 staining in patients with AAV indicated that NF-κB is activated in human NCGN also. We suggest that ANCA-stimulated neutrophils activate endothelial NF-κB, which contributes to NCGN and provides a potential therapeutic target in AAV.

Keywords: ANCA; endothelium; glomerulonephritis; transcription factors; vasculitis.

MeSH terms

  • Animals
  • Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / etiology*
  • Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / prevention & control
  • Cells, Cultured
  • Endothelium, Vascular
  • Glomerulonephritis / etiology*
  • Glomerulonephritis / pathology
  • Kidney Glomerulus / pathology
  • Mice
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / physiology*
  • Necrosis
  • Neutrophil Activation


  • NF-kappa B