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Granulocyte Macrophage Colony-Stimulating Factor Expression by Both Renal Parenchymal and Immune Cells Mediates Murine Crescentic Glomerulonephritis

Centre for Inflammatory Diseases, Monash University, Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia

Address correspondence to: Dr. Jennifer Timoshanko, Monash University, Department of Medicine, Monash Medical Center, 246 Clayton Road, Clayton, 3168 Victoria, Australia. Phone: 61-3-9594-5549; Fax: 61-3-9594-6495; E-mail: jennifer.timoshanko{at}med.monash.edu.au

Received for publication December 21, 2004. Accepted for publication June 16, 2005.

GM-CSF has previously been demonstrated to be important in crescentic glomerulonephritis (GN). As both renal parenchymal cells and infiltrating inflammatory cells produce GM-CSF, their separate contributions to inflammatory renal injury were investigated by creation of two different types of GM-CSF chimeric mice: (1) GM-CSF–deficient (GM-CSF^–/–)wild-type (WT) chimeras with leukocytes that are unable to produce GM-CSF and (2) WTGM-CSF^–/– chimeras with deficient renal cell GM-CSF expression. Crescentic anti–glomerular basement membrane GN was induced in WT, GM-CSF^–/–WT chimeras, WTGM-CSF^–/– chimeras, and GM-CSF^–/– mice by planting an antigen (sheep globulin) in their glomeruli. WT mice developed severe crescentic GN, whereas GM-CSF^–/– were protected from development of disease. Glomerular T cell recruitment, CD40⁺ glomerular cells, and renal IFN- and TNF expression were similar in both chimeras and WT mice but significantly reduced in GM-CSF^–/– mice, indicating that either leukocyte or renal sources of GM-CSF are sufficient to drive these aspects of the inflammatory response. Restricted expression of GM-CSF revealed a major role for renal cell–derived GM-CSF but a minor role for leukocyte-derived GM-CSF in the formation of cellular crescents; glomerular MHC II expression; serum creatinine; and monocyte chemoattractant protein-1, vascular cellular adhesion molecule, and IL-1 expression. Glomerular macrophage accumulation, proteinuria, and interstitial infiltrate were equivalent in both chimeric groups but intermediate between WT and GM-CSF^–/–, indicating that both sources are required for the full development of glomerular injury in crescentic GN.

Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673