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 homo...

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Autores principales:	Hiroyuki Inoshita, Byung-Gyu Kim, Michifumi Yamashita, Sung Hee Choi, Yasuhiko Tomino, John J Letterio, Steven N Emancipator
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/b19a19028de74cb88825c6d6571b696a
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spelling	oai:doaj.org-article:b19a19028de74cb88825c6d6571b696a2021-11-18T08:48:31ZDisruption of Smad4 expression in T cells leads to IgA nephropathy-like manifestations.1932-620310.1371/journal.pone.0078736https://doaj.org/article/b19a19028de74cb88825c6d6571b696a2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24223846/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203The 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.Hiroyuki InoshitaByung-Gyu KimMichifumi YamashitaSung Hee ChoiYasuhiko TominoJohn J LetterioSteven N EmancipatorPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 11, p e78736 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Hiroyuki Inoshita Byung-Gyu Kim Michifumi Yamashita Sung Hee Choi Yasuhiko Tomino John J Letterio Steven N Emancipator Disruption of Smad4 expression in T cells leads to IgA nephropathy-like manifestations.
description	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.
format	article
author	Hiroyuki Inoshita Byung-Gyu Kim Michifumi Yamashita Sung Hee Choi Yasuhiko Tomino John J Letterio Steven N Emancipator
author_facet	Hiroyuki Inoshita Byung-Gyu Kim Michifumi Yamashita Sung Hee Choi Yasuhiko Tomino John J Letterio Steven N Emancipator
author_sort	Hiroyuki Inoshita
title	Disruption of Smad4 expression in T cells leads to IgA nephropathy-like manifestations.
title_short	Disruption of Smad4 expression in T cells leads to IgA nephropathy-like manifestations.
title_full	Disruption of Smad4 expression in T cells leads to IgA nephropathy-like manifestations.
title_fullStr	Disruption of Smad4 expression in T cells leads to IgA nephropathy-like manifestations.
title_full_unstemmed	Disruption of Smad4 expression in T cells leads to IgA nephropathy-like manifestations.
title_sort	disruption of smad4 expression in t cells leads to iga nephropathy-like manifestations.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/b19a19028de74cb88825c6d6571b696a
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Disruption of Smad4 expression in T cells leads to IgA nephropathy-like manifestations.

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