Sun Qiang, Zhang Jianqian, Zhou Nan, Liu Xiaorong, Shen Ying
Department of nephrology, Beijing Children's Hospital, Capital Medical University, Beijing, China.
Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China.
PLoS One. 2015 Feb 3;10(2):e0112305. doi: 10.1371/journal.pone.0112305. eCollection 2015.
IgA nephropathy (IgAN) is one of the most common glomerular diseases leading to end-stage renal failure. Elevation of aberrantly glycosylated IgA1 is a key feature of it. The expression of the specific molecular chaperone of core1ß1, 3galactosyl transferase (Cosmc) is known to be reduced in IgAN. We aimed to investigate whether the methylation of CpG islands of Cosmc gene promoter region could act as a possible mechanism responsible for down-regulation of Cosmc and related higher secretion of aberrantly glycosylated IgA1in lymphocytes from children with IgA nephropathy. Three groups were included: IgAN children (n = 26), other renal diseases (n = 11) and healthy children (n = 13). B-lymphocytes were isolated and cultured, treated or not with IL-4 or 5-Aza-2'-deoxycytidine (AZA). The levels of DNA methylation of Cosmc promotor region were not significantly different between the lymphocytes of the three children populations (P = 0.113), but there were significant differences between IgAN lymphocytes and lymphocytes of the other two children populations after IL-4 (P<0.0001) or AZA (P<0.0001). Cosmc mRNA expression was low in IgAN lymphocytes compared to the other two groups (P<0.0001). The level of aberrantly glycosylated IgA1 was markedly higher in IgAN group compared to the other groups (P<0.0001). After treatment with IL-4, the levels of Cosmc DNA methylation and aberrantly glycosylated IgA1 in IgAN lymphocytes were remarkably higher than the other two groups (P<0.0001) with more markedly decreased Cosmc mRNA content (P<0.0001). After treatment with AZA, the levels in IgAN lymphocytes were decreased, but was still remarkably higher than the other two groups (P<0.0001), while Cosmc mRNA content in IgAN lymphocytes were more markedly increased than the other two groups (P<0.0001). The alteration of DNA methylation by IL-4 or AZA specifically correlates in IgAN lymphocytes with alterations in Cosmc mRNA expression and with the level of aberrantly glycosylated IgA1 (r = -0.948, r = 0. 707). Our results suggested that hypermethylation of Cosmc promoter region could be a key mechanism for the reduction of Cosmc mRNA expression in IgAN lymphocytes with associated increase in aberrantly glycosylated IgA1.
IgA肾病（IgAN）是导致终末期肾衰竭的最常见肾小球疾病之一。异常糖基化的IgA1升高是其关键特征。已知核心1β1,3-半乳糖基转移酶（Cosmc）的特异性分子伴侣在IgA肾病中表达降低。我们旨在研究Cosmc基因启动子区域CpG岛的甲基化是否可能是导致IgA肾病患儿淋巴细胞中Cosmc下调以及异常糖基化IgA1分泌增加的一种机制。研究纳入三组：IgA肾病患儿（n = 26）、其他肾病患儿（n = 11）和健康儿童（n = 13）。分离并培养B淋巴细胞，用或不用白细胞介素-4（IL-4）或5-氮杂-2'-脱氧胞苷（AZA）处理。三组儿童淋巴细胞中Cosmc启动子区域的DNA甲基化水平无显著差异（P = 0.113），但在IL-4（P<0.0001）或AZA（P<0.0001）处理后，IgA肾病淋巴细胞与其他两组儿童的淋巴细胞之间存在显著差异。与其他两组相比，IgA肾病淋巴细胞中Cosmc mRNA表达较低（P<0.0001）。与其他组相比，IgA肾病组中异常糖基化IgA1的水平明显更高（P<0.0001）。用IL-4处理后，IgA肾病淋巴细胞中Cosmc DNA甲基化水平和异常糖基化IgA1水平明显高于其他两组（P<0.0001），而Cosmc mRNA含量明显降低（P<0.0001）。用AZA处理后，IgA肾病淋巴细胞中的水平降低，但仍明显高于其他两组（P<0.0001），而IgA肾病淋巴细胞中Cosmc mRNA含量比其他两组明显增加（P<0.0001）。IL-4或AZA引起的DNA甲基化改变在IgA肾病淋巴细胞中与Cosmc mRNA表达改变以及异常糖基化IgA1水平存在特异性关联（r = -0.948，r = 0.707）。我们的结果表明，Cosmc启动子区域的高甲基化可能是IgA肾病淋巴细胞中Cosmc mRNA表达降低以及异常糖基化IgA1增加的关键机制。
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