骨髓间充质干细胞调节足细胞内质网应激治疗狼疮性肾炎的疗效和机制

Lupus nephritis is one of the most common clinical manifestations of systemic lupus erythematosus which affects its prognosis. In our clinical trial, we found that mesenchymal stem cell transplantation (MSCT) could improve prognosis of patients with lupus nephritis refractory to current standards of treatment, while the underling mechanisms were still unknown. Endoplasmic reticulum (ER) stress is a feature of many chronic inflammatory and autoimmune diseases. Podocytes injury is implicated in the development of proteinuria and glomerular sclerosis, and it was demonstrated that the ER stress of podocytes played an important role in glomerulonephritis. It was found that MSCT significantly attenuated renal ER stress in renal artery stenosis. In the present study, we investigated the expression of ER stress molecules, correlated cytokines and immunoglobulins in podocytes in MSCs treated MRL/lpr mice. To address the mechanisms, we also studied the influence of MSCs on the ER stress of podocytes in vitro in a MSC and podocyte coculture system. It may help to deeply indicate the mechanisms by which allogeneic MSCs treat lupus nephritis.

狼疮性肾炎是系统性红斑狼疮（SLE）最常见的临床表现之一，是影响SLE预后的重要因素，我们在临床工作中使用间充质干细胞（MSCs）移植治疗部分难治性狼疮性肾炎患者取得一定疗效，但其机制尚不明确。内质网（ER）应激是导致炎症及自身免疫性疾病的重要因素；足细胞的损伤与蛋白尿的产生及肾小球硬化的形成密切相关，足细胞ER应激损伤参与多种肾小球肾炎的发病；MSCs移植可以减轻肾动脉狭窄后肾脏的ER应激损伤。本研究通过MSCs移植治疗MRL/lpr狼疮鼠，观察MSCs对肾脏足细胞ER应激分子、相关细胞因子及免疫球蛋白的表达的影响；同时采用体外MSCs与足细胞共培养的方法，观察MSCs对足细胞ER应激水平的影响，并探讨其可能的机制。从而为临床推广应用MSCs移植治疗狼疮性肾炎提供新的理论依据。

狼疮性肾炎是影响系统性红斑狼疮（SLE）预后的重要因素，我们在临床工作中使用间充质干细胞（MSCs）移植治疗部分难治性狼疮性肾炎患者取得一定疗效，但其机制尚不明确。足细胞的损伤与蛋白尿的产生及肾小球硬化的形成密切相关。本项目第一部分研究中，我们成功建立了体外小鼠足细胞ER应激模型，发现在体外MSCs与足细胞间接或直接共培养均不能下调ER应激信号通路分子Bip、磷酸化/总IREα、磷酸化/总JNK、Full length/cleaved caspase-12及Chop的表达；MSCs对足细胞ER应激导致的早期凋亡及晚期凋亡均无明显作用。第二部分研究，我们分离培养小鼠腹腔巨噬细胞，在体外研究中发现MSCs可显著抑制巨噬细胞TNF-α和IL-1β等炎症因子的表达，并上调IL-4r和CD206等抗炎表型；与MSCs共培养后的巨噬细胞对足细胞的损伤明显降低，表现为足细胞标志物synaptopodin表达的增加以及凋亡百分率的下降。在动物实验中，我们建立MSCs移植狼疮鼠的治疗模型，发现MSCs移植治疗能上调狼疮鼠肾脏巨噬细胞CD206的表达；MSCs治疗组血清dsDNA水平、24小时尿蛋白及肾脏病理评分显著降低，肾小球IgG和C3的沉积显著减少，肾小球足细胞足突融合减少，肾脏足细胞标志物podocin和synaptopodin的表达显著增加。故我们推测，MSCs可通过诱导巨噬细胞抗炎表型，减轻足细胞损伤，从而治疗狼疮性肾炎。