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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Antineutrophil Cytoplasmic / immunology*
  • Cell Adhesion
  • Cell Degranulation*
  • Cell Movement
  • Cells, Cultured
  • Class Ib Phosphatidylinositol 3-Kinase
  • Female
  • Glomerulonephritis / enzymology*
  • Glomerulonephritis / immunology
  • Humans
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / metabolism
  • Macrophages / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neutrophils / physiology*
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism
  • Quinoxalines
  • Reactive Oxygen Species / metabolism
  • Thiazolidinediones


  • 5-quinoxalin-6-ylmethylenethiazolidine-2,4-dione
  • Antibodies, Antineutrophil Cytoplasmic
  • Isoenzymes
  • Phosphoinositide-3 Kinase Inhibitors
  • Quinoxalines
  • Reactive Oxygen Species
  • Thiazolidinediones
  • Class Ib Phosphatidylinositol 3-Kinase
  • PIK3CG protein, human
  • Pik3cg protein, mouse
  • Proto-Oncogene Proteins c-akt