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| Item Type: | Article |
|---|---|
| Title: | Phosphoinositol 3-kinase-gamma mediates antineutrophil cytoplasmic autoantibody-induced glomerulonephritis |
| Creators Name: | Schreiber, A., Rolle, S., Peripelittchenko, L., Rademann, J., Schneider, W., 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 |
| 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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