Endothelial NF-{kappa}B Blockade Abrogates ANCA-Induced GN

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-B mediates necrotizing crescentic GN (NCGN) and provides a specific treatment target. Reanalysis of kidneys from previously examined murine NCGN disease models revealed NF-B activation in affected kidneys, mostly as a p50/p65 heterodimer, and increased renal expression of NF-B–dependent tumor necrosis factor α (TNF-α). NF-B activation positively correlated with crescent formation, and nuclear phospho-p65 staining showed NF-B activation within CD31-expressing endothelial cells (ECs) in affected glomeruli. Therefore, we studied the effect of ANCA on NF-B activation in neutrophil/EC cocultures in vitro. ANCA did not activate NF-B in primed human neutrophils, but ANCA-stimulated primed neutrophils activated NF-B in ECs, at least in part via TNF-α release. This effect increased endothelial gene transcription and protein production of NF-B–regulated interleukin-8. Moreover, upregulation of endothelial NF-B 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-B significantly reduced urine abnormalities, renal myeloid cell influx, and NCGN....
Source: Journal of the American Society of Nephrology : JASN - Category: Urology & Nephrology Authors: Tags: Basic Research Source Type: research