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: Shunhua Guo, Tomasz A Wietecha, Kelly L Hudkins, Yujiro Kida, Min W Spencer, Warangkana Pichaiwong, Ichiro Kojima, Jeremy S Duffield, Charles E Alpers
• Journal: Kidney international (Kidney Int) Vol. 80 Issue 9 Pg. 946-958 (Nov 2011) ISSN: 1523-1755 [Electronic] United States
• PMID: 21814168 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• 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

Topics

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