miR-214-3p通过eIF3d与PTEN/JNK/c-Jun交互作用参与IgA肾病发病机制研究

IgA nephropathy(IgAN) is the most prevalent primary chronic glomerular disease worldwide. Its early pathological change is characterized by mesangial cell proliferation induced by deposition of polymeric Galactose-deficient IgA1 immune complex, while its regulatory mechanism remains unclear. Our experiments showed that miR-214-3p and eIF3d were upregulated in kidneys of IgAN mouse model. According to previous studies, we propose that miR-214-3p inhibiting PTEN, which regulates mesangial cell proliferation in IgAN through eIF3d specified interacting with c-Jun in JNK/c-Jun pathway, induced by polymeric Galactose-deficient IgA1 immune complex.Interaction between eIF3d and c-Jun in the transcriptional and posttranscriptional level creates a positive feedback loop contributing to mesangial cell proliferation in IgAN. Based on the in vitro and in vivo studies, we aim to explore how miR-214-3p involve in the pathogenesis of IgA nephropathy through the interaction between eIF3d and PTEN/JNK /c-Jun pathway by experimental techniques of luciferase reporter system, miRNA mimic/inhibitor and lentivirus transfection. This study would provide theoretical basis and therapeutic target for prevention and treatment of IgAN.

IgA肾病是全球最常见的原发性肾小球疾病。低糖基化IgA1免疫复合物沉积于肾小球致系膜细胞增殖是其早期主要病理特征,具体机制未明。我们预实验发现IgA肾病小鼠模型肾组织中miR-214-3p及eIF3d表达增加。结合前期研究我们推测：多聚低糖基化IgA1免疫复合物沉积于肾小球系膜区，致miR-214-3p表达增加，通过抑制PTEN表达活化JNK/c-Jun通路，加快细胞周期转换,促进IgA肾病系膜细胞增殖；同时c-Jun与eIF3d在转录水平及转录后水平交互作用，形成eIF3d与c-Jun正反馈环路促进系膜细胞增殖，造成肾脏损伤。本项目拟从体内体外两个层次开展研究，采用荧光素酶报告基因系统、miRNA模拟/抑制物、慢病毒载体等技术，探索miR-214-3p通过eIF3d与PTEN/JNK/c-Jun交互作用参与IgA肾病发病机制，为IgA肾病防治提供新的理论依据与治疗靶点。

IgA肾病是世界上最常见的原发性肾小球肾炎，亚洲IgAN的发生率和发展为终末期肾病(ESRD)的风险显著高于欧美。在中国，IgAN占原发性肾小球疾病的45.26%，是尿毒症的最常见病因。低糖基化IgA1免疫复合物沉积于肾小球致系膜细胞增殖是其早期主要病理特征，系膜细胞增殖机制和相关信号分子仍不清楚。我们成功构建了IgA肾病小鼠动物模型及人系膜细胞模型，我们通过miRNA测序以及原位杂交发现IgAN小鼠肾皮质中miR-214-3p显著上调。通过病毒转染、流式细胞术、荧光素酶报告基因等方法检测对应结果，发现通过抑制PTEN表达活化JNK/c-Jun通路，加快细胞周期转换,促进IgA肾病系膜细胞增殖；同时我们发现eIF3d在IgA肾病中表达增高，可以通过调节c-Jun促进系膜细胞增殖，造成肾脏损伤。本研究阐明了IgA肾病中系膜细胞增殖的分子机制，为IgA肾病的防治提供新的理论依据和治疗靶点。