miR-374b在IgA肾病低糖基化IgA1产生以及系膜细胞活化中的作用研究

IgA nephropathy is characterized by deposition of the IgA antibody in the glomerulus. IgA nephropathy is the most common glomerular disease in China, and also one of the leading causes of end-stage renal failure. Advanced theory focuses on the production of aberrantly glycosylated IgA1 and the following activation of mesangial cells. miRNAs are post-transcriptional regulators that bind to complementary sequences on target messenger RNA transcripts. Recently in our experiments we find that miR-374b is significantly up expressed in both peripheral B lymphocytes and isolated glomerulus of patients with IgA nephropathy. PTEN and Cosmc, which have been shown to play important role in cell activation and aberrantly glycosylated IgA1 production, are predicted to be the target genes of miR-374b. In the present study, studies will be conducted in vivo and in vitro, to look into the effect of miR-374b up expression on B cell proliferation and aberrantly glycosylated IgA1 production, and investigate the influence of miR-374b up expression on the proliferation and activation of renal mesangial cells. These studies will not only reveal the effect of miR-374b in the pathogenesis of IgA nephropathy, but also provide new targets for the intervention of this disease.

IgA肾病是我国最常见的原发性肾小球疾病，也是导致终末期肾衰的重要原因。IgA1糖基化异常以及系膜细胞活化是IgA肾病发病的关键环节。miRNAs可以通过抑制或断裂靶标mRNAs，调节基因表达。我们在前期工作中发现，IgA肾病外周B淋巴细胞和肾小球miR-374b显著上调。软件分析显示，与细胞增殖和活化相关的PTEN以及参与IgA1铰链区O-糖链半乳糖基化的分子伴侣Cosmc是miR-374b的预测靶基因。miR-374b可能通过靶向抑制PTEN和Cosmc，导致IgA肾病低糖基化IgA1产生以及系膜细胞活化。本项目将通过临床病例、体外细胞和模型小鼠实验，研究miR-374b上调在IgA肾病B淋巴细胞低糖基化IgA1产生中的作用，探讨miR-374b上调对系膜细胞活化的影响，从而阐明miR-374b在IgA肾病发病机制中的作用，为IgA肾病的干预研究提供新的思路和靶点。

IgA肾病是我国最常见的原发性肾小球疾病，也是导致终末期肾衰的重要原因。IgA1分子糖基化异常以及系膜细胞活化是IgA肾病发病的关键环节。miRNAs通过抑制或断裂靶标mRNAs，调节基因表达。本课题研究了miRNA在IgA肾病发病机制中作用。研究发现：1、miR-374b在IgA肾病外周B淋巴细胞中显著上调，通过靶向抑制Cosmc和PTEN，导致IgA1低糖基化和淋巴细胞增殖；2、miR-1301在IgA肾病肾小球系膜细胞中显著上调，通过靶向抑制DUSP2，导致系膜细胞活化。本课题的研究加深了对IgA肾病发病机制的认识，也为IgA肾病的干预研究提供了新靶点。