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Phosphoinositol 3-kinase-gamma mediates antineutrophil cytoplasmic autoantibody-induced glomerulonephritis

Item Type:Article
Title:Phosphoinositol 3-kinase-gamma mediates antineutrophil cytoplasmic autoantibody-induced glomerulonephritis
Creators Name:Schreiber, A. and Rolle, S. and Peripelittchenko, L. and Rademann, J. and Schneider, W. and Luft, F.C. and Kettritz, R.
Abstract:Antineutrophil cytoplasmic autoantibodies (ANCA) are associated with necrotizing crescentic glomerulonephritis (NCGN) and systemic vasculitis. We examined the role of phosphoinositol 3 kinase-gamma isoform (PI3Kgamma) in ANCA-activated neutrophil functions. Further, we tested whether its inhibition protects a mouse model of ANCA NCGN from developing NCGN. We transplanted bone marrow from wild-type mice or PI3Kgamma-deficient mice into myeloperoxidase-deficient mice immunized with myeloperoxidase. Bone marrow from PI3Kgamma(-/-) mice protected against development of the disease. Similarly, bone marrow transplanted from wild-type mice followed by treatment with the specific PI3Kgamma inhibitor AS605240 also protected these mice against NCGN in this model. AS605240 significantly abrogated myeloperoxidase- or proteinase 3-ANCA-stimulated superoxide production in vitro. Furthermore, ANCA-induced degranulation and GM-CSF-stimulated migration in a transwell assay of isolated human neutrophils were also abrogated by the drug. We found that PI3Kgamma plays a pivotal role in ANCA-induced NCGN and suggest that its specific inhibition may provide a novel treatment target.
Keywords:ANCA, Animal Model, Crescentic Glomerulonephritis, Inflammation, Neutrophils, PI3Kgamma, Animals, Mice
Source:Kidney International
ISSN:0085-2538
Publisher:Nature Publishing Group (U.S.A.)
Volume:77
Number:2
Page Range:118-128
Date:2 January 2010
Official Publication:https://doi.org/10.1038/ki.2009.420
PubMed:View item in PubMed

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