title: Intrinsic renal cells are the major source of tumor necrosis factor contributing to renal injury in murine crescentic glomerulonephritis.
abstract: 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.
authors.affiliation: Centre for Inflammatory Diseases, Department of Medicine, Monash Medical Centre, Monash University, 246 Clayton Road, Clayton, Victoria 3168, Australia.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Timoshanko
authors.forename: Jonathon D
authors.initials: JD
authors.lastname: Sedgwick
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Holdsworth
authors.forename: Peter G
authors.initials: PG
authors.lastname: Tipping
mesh_terms: 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*
chemical_list: D000199:Actins; D019040:E-Selectin; D000949:Histocompatibility Antigens Class II; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D005337:Fibrin; D003404:Creatinine