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Disruption of Smad4 expression in T cells leads to IgA nephropathy-like manifestations.

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 ?1, 4-galactosyltransferases (?4GalT) enzyme which is involved in the synthesis of glycosylated murine IgA, and we found reduced ?4GalT2 and ?4GalT4 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.

SUBMITTER: Inoshita H

PROVIDER: S-EPMC3817077 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Disruption of Smad4 expression in T cells leads to IgA nephropathy-like manifestations.

Inoshita Hiroyuki H Kim Byung-Gyu BG Yamashita Michifumi M Choi Sung Hee SH Tomino Yasuhiko Y Letterio John J JJ Emancipator Steven N SN

PloS one 20131104 11

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 ex ...[more]

PMID: 24223846

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Project description:Rationale & objectivePrevious studies have suggested that microRNA-21 (miR-21) plays an important role in kidney fibrosis. We examined the relationship between intrarenal miR-21 level and rate of kidney function loss in immunoglobulin A nephropathy (IgAN).Study designProspective cohort study.Setting & participants40 patients with IgAN and 10 with hypertensive nephrosclerosis as controls.PredictorsmiR-21 levels in kidney biopsy specimen and urinary sediment, quantified as ratio to the housekeeping gene.OutcomesKidney event-free survival and rate of kidney function decline.Analytic approachTime-to-event and correlation analysis.ResultsThe IgAN group had significantly higher intrarenal miR-21 expression compared with the hypertensive nephrosclerosis group (1.71 [IQR, 0.99-2.77] vs 0.31 [IQR, 0.25-1.32]; P < 0.0001), but urinary miR-21 levels were similar. Intrarenal miR-21 expression had significant but modest correlation with severity of glomerulosclerosis (r = 0.293; P = 0.05) and tubulointerstitial fibrosis (r = 0.341; P = 0.03). Patients with high intrarenal miR-21 expression had significantly higher risk for developing kidney end points compared with those with low expression (log-rank test, P = 0.017). Univariate Cox analysis showed that intrarenal miR-21 expression significantly predicted the development of kidney end points (unadjusted HR, 1.586; 95% CI, 1.179-2.134; P = 0.002). However, the result was just short of statistical significance after adjusting for the severity of histologic damage (P = 0.06). There was also a significant correlation between intrarenal miR-21 expression and the slope of kidney function decline by univariate analysis (r = -0.399; P = 0.02).LimitationsSmall sample size; uncertain cellular origin of miR-21.ConclusionsWe found that intrarenal miR-21 expression is increased in patients with IgAN, modestly correlated with the severity of histologic damage, and predictive of subsequent kidney function loss.

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Disruption of Smad4 expression in T cells leads to IgA nephropathy-like manifestations.

Publications

Disruption of Smad4 expression in T cells leads to IgA nephropathy-like manifestations.

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