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Disruption of Smad4 expression in T cells leads to IgA nephropathy-like manifestations.
- Source :
-
PloS one [PLoS One] 2013 Nov 04; Vol. 8 (11), pp. e78736. Date of Electronic Publication: 2013 Nov 04 (Print Publication: 2013). - Publication Year :
- 2013
-
Abstract
- The link between glomerular IgA nephropathy (IgAN) and T helper 2 (Th2) response has been implicated, however, the mechanisms are poorly defined because of the lack of an appropriate model. Here we report a novel murine model characterized by lineage-restricted deletion of the gene encoding MAD homologue 4 (Smad4) in T cells (Smad4(co/co;Lck-cre) ). Loss of Smad4 expression in T cells results in overproduction of Th2 cytokines and high serum IgA levels. We found that Smad4(co/co;Lck-cre) mice exhibited massive glomerular IgA deposition, increased albumin creatinine ratio, aberrant glycosylated IgA, IgA complexed with IgG1 and IgG2a, and polymeric IgA, all known features of IgAN in humans. Furthermore, we examined the β1, 4-galactosyltransferases (β4GalT) enzyme which is involved in the synthesis of glycosylated murine IgA, and we found reduced β4GalT2 and β4GalT4 mRNA levels in B cells. These findings indicate that Smad4(co/co;Lck-cre) mice could be a useful model for studying the mechanisms between IgAN and Th2 response, and further, disruption of Smad4-dependent signaling in T cells may play an important role in the pathogenesis of human IgAN and contributing to a Th2 T cell phenotype.
- Subjects :
- Animals
Cells, Cultured
Cytokines blood
Cytokines metabolism
Enzyme-Linked Immunosorbent Assay
Female
Galactosyltransferases genetics
Gene Expression Regulation, Enzymologic
Glomerular Mesangium pathology
Glomerular Mesangium ultrastructure
Glomerulonephritis, IGA blood
Glomerulonephritis, IGA metabolism
Immunoglobulin A blood
Immunoglobulin A metabolism
Isoenzymes genetics
Mice
Mice, 129 Strain
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Microscopy, Electron
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction genetics
Smad4 Protein metabolism
Th2 Cells metabolism
Glomerular Mesangium metabolism
Glomerulonephritis, IGA genetics
Smad4 Protein genetics
T-Lymphocytes metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 8
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 24223846
- Full Text :
- https://doi.org/10.1371/journal.pone.0078736