血清来源的Exosomes通过MicroRNA let-7a参与狼疮肾炎的机制研究

Lupus nephritis (LN) is a common and serious complication in patients with systemic lupus erythematosus (SLE). Our preliminay experimental results showed that serium exosomes from LN patients could induce and promote the development of LN in MRL/lpr mice, and could stimulate the proliferation of HRMC through activating PI3K/Akt pathway. MicroRNA let-7a, which combined with PI3K/Akt, was highly expressed in serum exosomes of LN patients. Therefore, we hypothesize that serium exosomes from LN patients can induce HRMC proliferation through highly expressed let-7a, and result in the secretion of variety inflammatory factors and the immune dysfunction. We intend to verify above hypothesis from three aspects: ①To study the effect of serum exosomes on the occurrence and development of LN and the proliferation of HRMC; ②To study the role and mechanism of let-7a in serum exosomes in the occurrence and development of LN and the proliferation of HRMC; ③To study the relationship between the expression of let-7a in serum exosomes and the incidence and prognosis of LN. Following the project, we will expect to provide new ideas and targets for the diagnosis, prognosis judgment and intervention therapy of LN.

LN是SLE患者常见和严重的并发症。预实验发现LN患者血清exosomes可促进MRL/lpr鼠LN发生发展；通过激活PI3K/Akt通路诱导HRMC增殖；高表达let-7a，后者是与PI3K/Akt结合的miRNA。因此推论：LN患者血清exosomes高表达的let-7a可通过激活PI3K/Akt等通路诱导HRMC增殖，分泌大量炎症因子，引起免疫功能失调，促进LN进展。本课题拟从三方面验证上述假说：①研究血清exosomes对LN发生发展及HRMC增殖的影响；②研究血清exosomes中let-7a在LN发生发展及HRMC增殖中的作用和机制；③研究血清来源exosomes中let-7a的表达与临床LN发病及预后的相关性。课题研究结果将为LN的诊断、预后判断及干预治疗提供新的思路和靶点。

系统性红斑狼疮（systemic lupus erythematosus，SLE）是一种累及多器官、多系统、严重危害患者身体健康和生活质量的自身免疫性疾病。狼疮肾炎（lupus nephritis，LN）是SLE患者常见和严重的并发症，以肾小球系膜细胞增殖为主要特征。阐明LN疾病进程中调控肾小球系膜细胞增殖的分子机制，对于积极预防LN的发生、改善疾病预后具有重要意义。本项目在前期研究的基础上，研究血清来源的exosomes对狼疮肾炎发生发展及肾小球系膜细胞增殖和功能的影响，分析exosomes中高表达的miRNA let- 7a的作用及其作为狼疮肾炎诊断和预后判断的生物指标的可能性，探讨LN患者血清来源exosomes通过miR-let-7a调控狼疮肾炎发生和发展的分子机制。研究结果表明，狼疮肾炎患者血清来源的exosomes可促进MRL/Lpr鼠狼疮肾炎的发生发展以及肾小球系膜细胞的增殖和炎症反应；LN患者血清来源的exosomes存在异常，高表达miR-let-7a，血清来源的exosomes被系膜细胞摄取后，释放miR-let-7a，通过激活PI3K/Akt信号通路诱导肾小球系膜细胞异常增殖，从而分泌大量炎症因子，导致免疫功能失调，促进狼疮肾炎的发生发展；血清exosomes中miR-let-7a的表达水平与患者24h尿蛋白量和血沉等呈正相关。本项目研究结果为全面了解exosomes在LN发生和转归中的作用奠定基础，也为临床诊断和治疗LN提供新的思路和靶点。