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

Endothelial NF-κB Blockade Abrogates ANCA-Induced GN.

Author information

1
Experimental and Clinical Research Center, the Charité Universitätsmedizin Berlin and the Max-Delbrück Center for Molecular Medicine at the Charité, Berlin, Germany; mira.choi@charite.de.
2
Nephrology and Internal Intensive Care, Charité Universitätsmedizin Berlin, Berlin, Germany.
3
Experimental and Clinical Research Center, the Charité Universitätsmedizin Berlin and the Max-Delbrück Center for Molecular Medicine at the Charité, Berlin, Germany.
4
Max-Delbrück Center for Molecular Medicine, Berlin, Germany; and.
5
Department of Pathology and Medical Biology, Medical Biology Section, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Abstract

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

PMID:
28687535
PMCID:
PMC5661273
DOI:
10.1681/ASN.2016060690
[Indexed for MEDLINE]
Free PMC Article

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