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- Title
Development of Immune-Complex Glomerulonephritis in TN Receptor 1, but not TNF Receptor 2-Deficient Mice.
- Authors
Vielhauer, V.; Mayadas, T. N.
- Abstract
Objective: TNF is essential for the development of glomerulonephritis (GN). However, it is not known which cell types respond to TNF and which TNF receptors are involved in this process. Methods: We investigated the roles of TNF receptor 1 (TNFR1) and 2 (TNFR2) in a model of nephrotoxic serum nephritis induced by rabbit anti-GBM antiserum. Results: Mice deficient in either TNFR1 or TNFR2 developed minimal proteinuria at day 7 (7% and 1% of wild-type (wt) mice, respectively). In TNFR1-deficient mice proteinuria at day 14 was 53% of wt mice, but was similar to wt at day 21. In contrast, TNFR2-deficient mice had minimal proteinuria at day 14 and 21 (<1% of wt). Renal histology at day 21 revealed severe glomerular injury in wt mice, which was reduced in TNFR1-deficient mice (68% of wt), but nearly absent in TNFR2-deficient mice (7% of wt). Renal macrophage and T cell infiltrates were prominent in wt and TNFR1-deficient mice, but were significantly less in TNFR2-deficient mice at day 21. Circulating autologous IgG to rabbit IgG was decreased in TNFR1-deficient mice by 60%, but not in the disease-protected TNFR2-deficient mice. TNFR2 expression on alpha beta T cells was not required for GN since alpha beta T cell-deficient mice reconstituted with wt or TNFR2-deficient T cells developed disease, whereas alpha beta T cell-deficient control mice did not. Furthermore, bone marrow chimeras revealed that intrinsic renal cell, but not leukocyte-expressed TNFR2 is required for the development of GN. Conclusions: These results demonstrate that TNFR1 is not required for disease induction and progression of GN, though it has a contributing role in the adaptive immune response during the initiation phase. In contrast, TNFR2 expressed on intrinsic renal cells is essential for the development and progression of GN. Blocking TNFR2, but not TNFR1 may be a promising therapeutic strategy in immune-mediated GN.
- Subjects
TUMOR necrosis factors; GLOMERULONEPHRITIS; NEPHROTOXICOLOGY; PROTEINURIA; BONE marrow; KIDNEY glomerulus diseases
- Publication
Kidney & Blood Pressure Research, 2004, Vol 27, Issue 5/6, p307
- ISSN
1420-4096
- Publication type
Article