Intrinsic renal cells are the major source of tumor necrosis factor contributing to renal injury in murine crescentic glomerulonephritis.
Macrophages are prominent participants in crescentic glomerulonephritis (GN) and have been suggested to be the major source of TNF in this cell-mediated form of glomerular inflammation. Intrinsic renal cells also have the capacity to produce TNF. For dissecting the contribution of local versus bone marrow (BM)-derived TNF in inflammatory renal injury, TNF chimeric mice were created by transplanting normal wild-type (WT) BM into irradiated TNF-deficient recipients (WT-->TNF-/- chimeras) and vice versa (TNF-/- -->WT chimeras). A model of crescentic GN induced by an intravenous injection of sheep anti-murine glomerular basement membrane antibody was studied in WT mice, mice with complete TNF deficiency (TNF-/-), and chimeric mice. Crescentic GN was attenuated in TNF-/- mice with fewer crescents (crescents, 13.7 +/- 1.7% of glomeruli) and reduced functional indices of renal injury (serum creatinine, 15.2 +/- 0.8 micromol/L). Similar protection (crescents, 14.3 +/- 1.9% of glomeruli; serum creatinine, 18.9 +/- 1.1 micromol/L) was observed in chimeric mice with intact BM but absent renal-derived TNF (WT-->TNF-/- chimeras), suggesting a minor contribution of infiltrating leukocytes to TNF-mediated renal injury. Chimeric mice with TNF-deficient leukocytes but intact intrinsic renal cell-derived TNF (crescents, 20.5 +/- 2.0% of glomeruli; serum creatinine, 21.6 +/- 1.4 micromol/L) developed similar crescentic GN to WT mice (crescents, 22.3 +/- 1.4% of glomeruli; serum creatinine, 24.8 +/- 1.9 micromol/L). Cutaneous delayed-type hypersensitivity after subdermal challenge with the nephritogenic antigen was attenuated in the absence of BM cell-derived TNF but unaffected in WT-->TNF-/- chimeric mice. These studies suggest that intrinsic renal cells are the major cellular source of TNF contributing to inflammatory injury in crescentic GN.
Timoshanko
Jennifer R
JR
Centre for Inflammatory Diseases, Department of Medicine, Monash Medical Centre, Monash University, 246 Clayton Road, Clayton, Victoria 3168, Australia.
Sedgwick
Jonathon D
JD
Holdsworth
Stephen R
SR
Tipping
Peter G
PG
D000199:Actins / Q000378:metabolism; D000818:Animals; D001485:Basement Membrane / Q000378:metabolism; D016026:Bone Marrow Transplantation; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D003404:Creatinine / Q000097:blood; D019040:E-Selectin / Q000378:metabolism; D005337:Fibrin / Q000378:metabolism; D005921:Glomerulonephritis / Q000276:immunology* / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D006968:Hypersensitivity, Delayed; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D007668:Kidney / Q000166:cytology* / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D011507:Proteinuria / Q000378:metabolism; D012756:Sheep; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D000199:Actins; D019040:E-Selectin; D000949:Histocompatibility Antigens Class II; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D005337:Fibrin; D003404:Creatinine