Mycophenolic acid reverses IgA1 aberrant glycosylation through up-regulating Cosmc expression in IgA nephropathy
Mycophenolic acid reverses IgA1 aberrant glycosylation through up-regulating Cosmc expression in IgA nephropathy
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DOI：
10.1007/s11255-012-0313-y
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发表时间：
2013-04-01
影响因子：
2
通讯作者：
Qin, Wei
中科院分区：
文献类型：
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作者：
Xie, Linshen;Tan, Chunyu;Qin, Wei
伊加肾病（IgA nephropathy，IgAN）的主要发病机制之一是核心I β 3-Gal-T-specific molecular chaperone（Cosmc）表达受损，导致伊加（1）O-糖基化异常，本研究旨在探讨霉酚酸（mycophenolic acid，MPA）是否能上调IgAN患者外周血淋巴细胞Cosmc表达，逆转IgA（1）O-糖基化异常。分离18名IgAN患者和12名正常对照的外周血淋巴细胞，并在有或没有脂多糖（LPS）和MPA的情况下培养3-7天。实时定量RT-PCR和western blot检测Cosmc mRNA和蛋白表达水平。采用酶联免疫吸附试验（ELISA）和VV凝集素结合试验测定伊加（1）和O-糖基化水平。Cosmc表达水平与伊加（1）O-糖基化水平进行相关性分析，IgA肾病患者Cosmc mRNA表达水平和伊加（1）O-糖基化水平均显著低于正常对照组。LPS治疗可明显抑制IgAN患者外周血淋巴细胞Cosmc表达，增加伊加（1）分泌，导致伊加（1）异常糖基化水平显著升高。MPA的加入可使Cosmc的表达水平沿着增加，同时伊加（1）的分泌减少，导致异常糖基化的逆转。Cosmc表达与伊加（1）O-糖基化水平呈正相关，MPA可上调IgA肾病患者外周血淋巴细胞Cosmc表达，逆转伊加（1）O-糖基化水平异常，这可能是霉酚酸酯（MMF）治疗IgA肾病的机制之一。
Impaired core I beta 3-Gal-T-specific molecular chaperone (Cosmc) expression-caused IgA(1) aberrant O-glycosylation is one of the main pathogeneses of IgA nephropathy (IgAN).This study tried to elucidate whether mycophenolic acid (MPA) could up-regulate Cosmc expression of peripheral lymphocytes in IgAN patients and reverse the dys-O-glycosylation.Peripheral lymphocytes of eighteen IgAN patients and twelve normal controls were isolated and cultured for 3-7 days with or without lipopolysaccharide (LPS) and MPA. Cosmc mRNA and protein expression levels were measured by real-time RT-PCR and western blot. IgA(1) and O-glycosylation level were determined by enzyme-linked immunosorbent assay (ELISA) and VV lectin-binding test. Correlation analysis was performed between Cosmc expression levels and IgA(1) O-glycosylation level.Cosmc mRNA expression and IgA(1) O-glycosylation level in IgAN patients were significantly lower than normal controls. Treatment of LPS could obviously inhibit the Cosmc expression and increase the IgA(1) secretion in peripheral lymphocytes of IgAN patients, which resulted in a significantly increase in IgA(1) aberrant glycosylation level. Addition of MPA could significantly increase the Cosmc expression level along with a decrease in IgA(1) secretion, leading to a reverse of aberrant glycosylation. A significant positive correlation between the Cosmc expression and IgA(1) O-glycosylation level was noticed.MPA can up-regulate the Cosmc expression and reverse the IgA(1) aberrant O-glycosylation level in peripheral lymphocytes of IgAN patients, which might be the underlying mechanism of mycophenolate mofetil (MMF) therapy used in treating IgAN.