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Kidney Int. 2010 Jan;77(2):118-28. doi: 10.1038/ki.2009.420. Epub 2009 Nov 11.

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

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  • 1Department of Nephrology and Hypertension, Medical Faculty of the Charité, Franz Volhard Clinic, Max Delbrück Center for Molecular Medicine, Schwanebecker Chaussee 50, Berlin, Germany. adrian.schreiber@gmx.de

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.

PMID:
19907415
[PubMed - indexed for MEDLINE]
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