title: Macrophages are essential contributors to kidney injury in murine cryoglobulinemic membranoproliferative glomerulonephritis.
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.
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington, USA.
authors.forename: Shunhua
authors.initials: S
authors.lastname: Guo
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington, USA.
authors.forename: Tomasz A
authors.initials: TA
authors.lastname: Wietecha
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington, USA.
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Hudkins
authors.affiliation: Division of Nephrology, Department of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Yujiro
authors.initials: Y
authors.lastname: Kida
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington, USA.
authors.forename: Min W
authors.initials: MW
authors.lastname: Spencer
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington, USA.
authors.forename: Warangkana
authors.initials: W
authors.lastname: Pichaiwong
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington, USA.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kojima
authors.affiliation: Division of Nephrology, Department of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Duffield
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington, USA. Electronic address: calp@u.washington.edu.
authors.forename: Charles E
authors.initials: CE
authors.lastname: Alpers
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D039481:CD11b Antigen / Q000235:genetics; D024141:Collagen Type IV / Q000378:metabolism; D003449:Cryoglobulinemia / Q000150:complications / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D019610:Cytoprotection; D004167:Diphtheria Toxin / Q000008:administration & dosage; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D015432:Glomerulonephritis, Membranoproliferative / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000276:immunology / Q000473:pathology; D008168:Lung / Q000276:immunology / Q000473:pathology; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000235:genetics; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D011507:Proteinuria / Q000276:immunology / Q000517:prevention & control; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D000094632:Thymic Stromal Lymphopoietin
chemical_list: D000199:Actins; D039481:CD11b Antigen; D024141:Collagen Type IV; D016207:Cytokines; D004167:Diphtheria Toxin; C587883:HBEGF protein, human; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; C544013:alpha-smooth muscle actin, mouse; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D000094632:Thymic Stromal Lymphopoietin