Phosphoinositol 3-kinase-gamma mediates antineutrophil cytoplasmic autoantibody-induced glomerulonephritis.
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.
Schreiber
Adrian
A
Department 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
Rolle
Susanne
S
Peripelittchenko
Ludmilla
L
Rademann
Joerg
J
Schneider
Wolfgang
W
Luft
Friedrich C
FC
Kettritz
Ralph
R
D000818:Animals; D019268:Antibodies, Antineutrophil Cytoplasmic / Q000276:immunology*; D002448:Cell Adhesion; D015550:Cell Degranulation; D002465:Cell Movement; D002478:Cells, Cultured; D058544:Class Ib Phosphatidylinositol 3-Kinase; D005260:Female; D005921:Glomerulonephritis / Q000201:enzymology* / Q000276:immunology; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008264:Macrophages / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011810:Quinoxalines; D017382:Reactive Oxygen Species / Q000378:metabolism; D045162:Thiazolidinediones
D019268:Antibodies, Antineutrophil Cytoplasmic; D058544:Class Ib Phosphatidylinositol 3-Kinase; D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011810:Quinoxalines; D017382:Reactive Oxygen Species; D045162:Thiazolidinediones; C505144:5-quinoxalin-6-ylmethylenethiazolidine-2,4-dione; C546760:PIK3CG protein, human; C546764:Pik3cg protein, mouse