基于p62-Keap1-Nrf2通路研究青蒿素衍生物在治疗狼疮性肾炎中的作用机制

Lupus nephritis (LN) is a severe autoimmune disease initiated by production of autoantibodies and glomerular immune-complex deposition. The deposition of the immune complex triggers a cascade of events in the inflammatory response that are accompanied by the generation of reactive oxygen species (ROS), which have a pivotal role in both acute and chronic glomerular injuries in LN. Nrf2 is a major regulator of the antioxidant response and is a primary cellular defense mechanism. We found in our previous study that the exacerbated renal damage and accumulated inflammatory cytokines resulted in imbalance of Nrf2 pathway, and lose of redox homeostasis in LN. The Artemisinin analog SM934 could enhance the Nrf2 signaling, promote the activity of detoxifying enzymes, and improve renal function of LN mice. On the basis of these observation, further studies would be carried out to elucidate the modulatory mechanism of SM934 on the components of Nrf2 pathway, interference on the inflammation induce oxidative stress in the kidney, and regulation of aberrant cellular activation and differentiation. This project will provide experimental evidence for the cross talk of dysregulation of Nrf2 signaling and pathologic immune cell polarization in LN, and enlighten the investigation of etiology and therapeutic strategy for LN.

狼疮性肾炎（Lupus nephritis）是由免疫复合物沉积诱发的炎症反应和肾脏病理改变。炎症环境导致活性氧（ROS）积累，活化Keap1-Nrf2抗氧化损伤通路，启动抗氧化基因参与细胞保护过程。前期研究发现，狼疮性肾炎中组织损伤及炎症因子表达升高，导致Nrf2通路失调，氧化还原平衡破坏，组织炎症加剧。青蒿素衍生物SM934能够增强Nrf2通路，提高抗氧化酶类的含量及活性，继而抑制炎症应答、改善肾脏病理损伤。基于上述发现，本项目围绕Nrf2分子在抗氧化防御中的关键作用，运用狼疮性肾炎动物模型，探讨SM934对Nrf2通路关键分子表达的影响；对炎症诱导氧化损伤效应的干预；对Nrf2通路失调引起的细胞活化及分化异常的调控作用。同时，本研究探讨了Nrf2通路失调与病理性淋巴细胞异常分化的内在关联，拓宽了狼疮性肾炎病理机制的研究思路，为疾病的新型治疗策略提供有力线索。

狼疮性肾炎是由免疫复合物沉积诱发的炎症反应和肾脏病理改变。炎症环境导致活性氧积累，活化Keap1-Nrf2抗氧化损伤通路，启动抗氧化基因参与细胞保护过程。前期研究发现，狼疮性肾炎中组织损伤及炎症因子表达升高，导致Nrf2通路失调，氧化还原平衡破坏，组织炎症加剧。青蒿素衍生物SM934能够增强Nrf2通路，提高抗氧化酶类的含量及活性，继而抑制炎症应答、改善肾脏病理损伤。本项目围绕Nrf2分子在抗氧化防御中的关键作用，运用狼疮性肾炎动物模型，发现在NZW×BXSB F1小鼠自发狼疮性肾炎模型中，运用SM934干预治疗能够有效降低实验动物蛋白尿水平，提高模型小鼠生存率；SM934通过调控Nrf2-HO-1抗氧化防御调控系统，下调肾脏组织中炎症因子转录及蛋白表达水平，抑制炎症因子释放，减轻模型小鼠肾脏损伤。同时，本研究发现，SM934对狼疮模型小鼠MRL/lpr的治疗作用，与其控制淋巴器官和肾脏中ABCs的扩增、改变异常的细胞能量代谢密切相关。ABCs细胞是与SLE患者的疾病活动度和治疗应答指数高度相关的记忆性B细胞亚群。通过在疾病各进展阶段采用SM934干预，检测狼疮相关自身抗体指标及肾炎相关血生化、尿液指标，综合考察免疫细胞表型和能量代谢模式，结果发现：MRL/lpr小鼠脾脏和肾脏中ABCs细胞数量快速增加，与疾病活动指征呈正相关性；脾脏中B细胞的糖酵解和线粒体呼吸随疾病进展显著增强，而肾脏中浸润的B细胞的代谢水平低于正常小鼠，两者呈现出相反的能量代谢变化趋势；SM934治疗显著减少MRL/lpr小鼠免疫器官和肾脏中的ABCs细胞，SM934治疗逆转了疾病进展期MRL/lpr小鼠免疫器官和肾脏中B细胞的异常能量代谢模式。本研究探讨了Nrf2通路失调与病理性淋巴细胞异常分化的内在关联，拓宽了狼疮性肾炎病理机制的研究思路，为疾病的新型治疗策略提供有力线索。