Abstract
Mice transgenic for thymic stromal lymphopoietin (TSLP), under regulation of the lymphocyte-specific promoter Lck, develop cryoglobulinemia and membranoproliferative glomerulonephritis (MPGN) similar to the disease in patients. To determine whether infiltrating macrophages, a hallmark of this disease, are deleterious or beneficial in the injury process, we developed Lck-TSLP transgenic mice expressing the human diphtheria toxin receptor (DTR) under control of the monocyte/macrophage-restricted CD11b promoter (Lck-TSLP;CD11b-DTR). Treatment with DT resulted in a marked reduction of monocytes/macrophages in the peritoneal cavity of both CD11b-DTR and Lck-TSLP;CD11b-DTR mice and marked reduction of macrophage infiltration in glomeruli of Lck-TSLP;CD11b-DTR mice. Lck-TSLP;CD11b-DTR mice, with or without toxin treatment, had similar levels of cryoglobulinemia and glomerular immunoglobulin deposition as Lck-TSLP mice. Lck-TSLP;CD11b-DTR mice, treated with toxin, had reduced mesangial matrix expansion, glomerular collagen IV accumulation, expression of the activation marker α-smooth muscle actin and transforming growth factor-β1 in mesangial cells, and proteinuria compared with control mice. Thus, macrophage ablation confers protection in this model and indicates a predominately deleterious role for macrophages in the progression of kidney injury in cryoglobulinemic MPGN.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Actins / metabolism
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Animals
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CD11b Antigen / genetics
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Collagen Type IV / metabolism
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Cryoglobulinemia / complications
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Cryoglobulinemia / genetics
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Cryoglobulinemia / immunology*
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Cryoglobulinemia / metabolism
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Cryoglobulinemia / pathology
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Cytokines / genetics
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Cytokines / metabolism
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Cytoprotection
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Diphtheria Toxin / administration & dosage
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Disease Models, Animal
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Disease Progression
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Female
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Glomerulonephritis, Membranoproliferative / genetics
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Glomerulonephritis, Membranoproliferative / immunology*
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Glomerulonephritis, Membranoproliferative / metabolism
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Glomerulonephritis, Membranoproliferative / pathology
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Glomerulonephritis, Membranoproliferative / prevention & control
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Heparin-binding EGF-like Growth Factor
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Humans
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Intercellular Signaling Peptides and Proteins / genetics
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Intercellular Signaling Peptides and Proteins / metabolism
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Kidney / drug effects
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Kidney / immunology*
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Kidney / metabolism
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Kidney / pathology
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Liver / immunology
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Liver / pathology
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Lung / immunology
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Lung / pathology
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Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / genetics
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Macrophages / drug effects
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Macrophages / immunology*
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Promoter Regions, Genetic
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Proteinuria / immunology
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Proteinuria / prevention & control
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Thymic Stromal Lymphopoietin
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Time Factors
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Transforming Growth Factor beta1 / metabolism
Substances
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Actins
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CD11b Antigen
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Collagen Type IV
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Cytokines
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Diphtheria Toxin
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HBEGF protein, human
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Hbegf protein, mouse
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Heparin-binding EGF-like Growth Factor
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Intercellular Signaling Peptides and Proteins
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Tgfb1 protein, mouse
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Transforming Growth Factor beta1
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alpha-smooth muscle actin, mouse
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Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
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Thymic Stromal Lymphopoietin