Abstract
The molecular mechanism(s) of immunoglobulin A (IgA) nephropathy, the most common primary renal glomerular disease worldwide, is unknown. Its pathologic features include hematuria, high levels of circulating IgA-fibronectin (Fn) complexes, and glomerular deposition of IgA, complement C3, Fn and collagen. We report here that two independent mouse models (gene knockout and antisense transgenic), both manifesting deficiency of an anti-inflammatory protein, uteroglobin (UG), develop almost all of the pathologic features of human IgA nephropathy. We further demonstrate that Fn-UG heteromerization, reported to prevent abnormal glomerular deposition of Fn and collagen, also abrogates both the formation of IgA-Fn complexes and their binding to glomerular cells. Moreover, UG prevents glomerular accumulation of exogenous IgA in UG-null mice. These results define an essential role for UG in preventing mouse IgA nephropathy and warrant further studies to determine if a similar mechanism(s) underlies the human disease.
MeSH terms
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Animals
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Antigen-Antibody Complex / analysis
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Antigen-Antibody Complex / blood
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Antigen-Antibody Complex / drug effects
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Antigen-Antibody Complex / immunology
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Cells, Cultured
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Collagen / genetics
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Collagen / metabolism
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Complement C3 / analysis
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Complement C3 / immunology
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Disease Models, Animal
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Fibronectins / analysis
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Fibronectins / blood
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Fibronectins / genetics
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Fibronectins / immunology
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Gene Deletion
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Glomerular Mesangium / cytology
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Glomerular Mesangium / drug effects
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Glomerular Mesangium / immunology
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Glomerular Mesangium / pathology
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Glomerulonephritis, IGA / genetics
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Glomerulonephritis, IGA / immunology
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Glomerulonephritis, IGA / pathology*
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Glomerulonephritis, IGA / physiopathology
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Hematuria / pathology
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Hematuria / urine
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Humans
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Immunoglobulin A / analysis
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Immunoglobulin A / blood
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Immunoglobulin A / drug effects
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Immunoglobulin A / immunology*
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Kidney Glomerulus / immunology
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Kidney Glomerulus / metabolism
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Kidney Glomerulus / pathology*
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Kidney Glomerulus / physiopathology
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Mice
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Mice, Knockout
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Mice, Transgenic
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Platelet-Derived Growth Factor / analysis
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Platelet-Derived Growth Factor / genetics
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Proto-Oncogene Proteins / analysis
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins c-sis
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RNA, Antisense / genetics
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Uteroglobin / deficiency
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Uteroglobin / genetics
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Uteroglobin / pharmacology
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Uteroglobin / physiology*
Substances
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Antigen-Antibody Complex
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Complement C3
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Fibronectins
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Immunoglobulin A
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Platelet-Derived Growth Factor
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-sis
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RNA, Antisense
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RNA, Messenger
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Collagen
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Uteroglobin