In:
Journal of the American Society of Nephrology, Ovid Technologies (Wolters Kluwer Health), Vol. 28, No. 11 ( 2017-11), p. 3191-3204
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- κ B mediates necrotizing crescentic GN (NCGN) and provides a specific treatment target. Reanalysis of kidneys from previously examined murine NCGN disease models revealed NF- κ B activation in affected kidneys, mostly as a p50/p65 heterodimer, and increased renal expression of NF- κ B–dependent tumor necrosis factor α (TNF- α ). NF- κ B activation positively correlated with crescent formation, and nuclear phospho-p65 staining showed NF- κ B activation within CD31-expressing endothelial cells (ECs) in affected glomeruli. Therefore, we studied the effect of ANCA on NF- κ B activation in neutrophil/EC cocultures in vitro . ANCA did not activate NF- κ B in primed human neutrophils, but ANCA-stimulated primed neutrophils activated NF- κ B in ECs, at least in part via TNF- α release. This effect increased endothelial gene transcription and protein production of NF- κ B–regulated interleukin-8. Moreover, upregulation of endothelial NF- κ B promoted neutrophil adhesion to EC monolayers, an effect that was inhibited by a specific IKK β inhibitor. In a murine NCGN model, prophylactic application of E-selectin–targeted immunoliposomes packed with p65 siRNA to downregulate endothelial NF- κ B significantly reduced urine abnormalities, renal myeloid cell influx, and NCGN. Increased glomerular endothelial phospho-p65 staining in patients with AAV indicated that NF- κ B is activated in human NCGN also. We suggest that ANCA-stimulated neutrophils activate endothelial NF- κ B, which contributes to NCGN and provides a potential therapeutic target in AAV.
Type of Medium:
Online Resource
ISSN:
1046-6673
,
1533-3450
DOI:
10.1681/ASN.2016060690
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2017
detail.hit.zdb_id:
2029124-3
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