Macrophages are essential contributors to kidney injury in murine cryoglobulinemic membranoproliferative glomerulonephritis

Kidney Int. 2011 Nov;80(9):946-958. doi: 10.1038/ki.2011.249. Epub 2011 Aug 3.

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

  • Research Support, N.I.H., Extramural

MeSH terms

  • Actins / metabolism
  • Animals
  • CD11b Antigen / genetics
  • Collagen Type IV / metabolism
  • Cryoglobulinemia / complications
  • Cryoglobulinemia / genetics
  • Cryoglobulinemia / immunology*
  • Cryoglobulinemia / metabolism
  • Cryoglobulinemia / pathology
  • Cytokines / genetics
  • Cytokines / metabolism
  • Cytoprotection
  • Diphtheria Toxin / administration & dosage
  • Disease Models, Animal
  • Disease Progression
  • Female
  • Glomerulonephritis, Membranoproliferative / genetics
  • Glomerulonephritis, Membranoproliferative / immunology*
  • Glomerulonephritis, Membranoproliferative / metabolism
  • Glomerulonephritis, Membranoproliferative / pathology
  • Glomerulonephritis, Membranoproliferative / prevention & control
  • Heparin-binding EGF-like Growth Factor
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Kidney / drug effects
  • Kidney / immunology*
  • Kidney / metabolism
  • Kidney / pathology
  • Liver / immunology
  • Liver / pathology
  • Lung / immunology
  • Lung / pathology
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / genetics
  • Macrophages / drug effects
  • Macrophages / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Promoter Regions, Genetic
  • Proteinuria / immunology
  • Proteinuria / prevention & control
  • Thymic Stromal Lymphopoietin
  • Time Factors
  • Transforming Growth Factor beta1 / metabolism

Substances

  • Actins
  • CD11b Antigen
  • Collagen Type IV
  • Cytokines
  • Diphtheria Toxin
  • HBEGF protein, human
  • Hbegf protein, mouse
  • Heparin-binding EGF-like Growth Factor
  • Intercellular Signaling Peptides and Proteins
  • Tgfb1 protein, mouse
  • Transforming Growth Factor beta1
  • alpha-smooth muscle actin, mouse
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
  • Thymic Stromal Lymphopoietin