FOXO3a在系统性红斑狼疮肾损害发病中的作用机制

Lupus nephritis (LN) is a common and potentially severe complication of systemic lupus erythematosus (SLE), contributing greatly to the morbidity and mortality of the disease. The pathogenesis of LN includes production of autoantibodies, deposition of immune complexes (IC), activation of complement and infiltration of inflammatory cells in the kidneys, which contributes to renal fibrosis. The exact mechanism of kidney injury remains to not be fully elucidated. FOXO3a play critical roles in immune cell homeostasis, modulating inflammation in some disease. Very little is known about the influence FOXO3a on the lupus renal lesions mechanism.In our study, we aim to determine the quantities of FOXO3a expression in peripheral blood mononuclear cells (PBMCs) from LN and in kindny of MRL/lpr mice as well as the activity of PI3K/Akt/FOXO3a signaling pathway. The study aim to elucate the regulation of FOXO3a on the proinflammatory factors and TGF-β expression. The MRL/lpr mouse will be sacrificed by injecting them with inhibitor of PI3K intravenously. We would clarify the renal injury and imflammation by which FOXO3a are mediated. We would decide whether or not FOXO3a is a new therapeutic target in lupus renal injury.

狼疮肾炎(LN)是由于免疫紊乱导致自身抗体产生、免疫复合物沉积、补体激活、炎症细胞浸润，终致肾损伤。叉头框O3a(FOXO3a)与炎症反应、免疫调节有密切联系，但FOXO3a在LN发病中的作用尚不清楚。本研究探讨人LN外周血单个核细胞和自发性狼疮MRL/lpr小鼠肾组织FOXO3a表达情况以及PI3K/Akt/FOXO3a信号通路活化。分离SLE患者血中抗DNA抗体，刺激人肾小球系膜细胞，探讨自身抗体对肾小球系膜细胞中FOXO3a表达作用。利用PI3K/Akt/FOXO3a信号通路抑制剂和FOXO3asiRNA，探讨FOXO3a的活化和对炎症因子和促纤维化因子TGF-的调控作用。通过给MRL/lpr小鼠体内注射PI3K抑制剂，观察对肾脏炎症、功能和病理损害的影响，进一步阐明FOXO3a在LN发病机制中的作用，提出以FOXO3a为靶点的LN治疗新思路。

狼疮肾炎是由于免疫紊乱导致自身抗体产生、免疫复合物沉积、补体激活、炎症细胞浸润，终致肾损伤。叉头框O3a蛋白(FOXO3a)与炎症反应、免疫调节有密切联系，但FOXO3a在狼疮肾炎发病中的作用尚不清楚。动物研究，通过用药物LY294002抑制剂处理MRL/Ipr小鼠，通过阻断PI3K/AKT/FOXO3a信号通路后，减少胞浆FOXO3a表达，验证细胞核内FOXO3a表达增加，可减轻MRL/Ipr小鼠肾脏炎症。研究结果如下1）抑制MRL/lpr狼疮鼠肾组织AKT/FOXO3a信号通路，肾组织α-SMA和TGF-β的表达减少；2）减轻肾病理组织炎症细胞CD3T细胞和CD68巨噬细胞的浸润，同时纤维化指标α-SMA和增殖指标PCNA表达下调；3）降低狼疮鼠蛋白尿和肌酐水平。细胞研究，用LY294002预处理经dsDNA诱导的肾小球系膜细胞后，结果证实抑制细胞胞浆内FOXO3a表达，可降低肾小球系膜细胞IL-1和TGF-β表达。在临床研究证实在狼疮患者PBMC细胞中FOXO3a减少。上述研究证实FOXO3a表达减少是狼疮肾炎炎症和纤维化过程关键因素。FOXO3a是将来狼疮肾炎治疗的靶点。