Disruption of Smad4 expression in T cells leads to IgA nephropathy-like manifestations.
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.
Department of Pathology, Case Western Reserve University, Cleveland, Ohio, United States of America ; Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Bunkyo-ku, Tokyo, Japan.
Hiroyuki
H
Inoshita
Byung-Gyu
BG
Kim
Michifumi
M
Yamashita
Sung Hee
SH
Choi
Yasuhiko
Y
Tomino
John J
JJ
Letterio
Steven N
SN
Emancipator
D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005700:Galactosyltransferases / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic; D005920:Glomerular Mesangium / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D005922:Glomerulonephritis, IGA / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D007070:Immunoglobulin A / Q000097:blood / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D051901:Smad4 Protein / Q000235:genetics* / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism*; D018418:Th2 Cells / Q000378:metabolism
D016207:Cytokines; D007070:Immunoglobulin A; D007527:Isoenzymes; D051901:Smad4 Protein; D005700:Galactosyltransferases