Fra-2在狼疮性肾炎足细胞凋亡中机制研究

LN is one of the most common and severe characteristics in SLE and a major cause of morbidity and mortality in patients with lupus.Until now the general pathogenesis of this disease still needs a better understanding. Based on much research, we know that the activator protein (AP-1)-related transcription factor Fra-2 directly binds to the PPAR-γ promoter induced adipocyte apoptosis. And PPAR-γ and TGF-β involved in the podocyte apoptosis. However whether Fra-2 involved in the podocyte apoptosis in patients with LN is still poorly understood. Our previous study found that Fra-2 levels of podocytes in patients with LN was significantly higher than in patients with other kidney disease and the controls. Futheremore, we also found Fra-2 induced podocyte apoptosis after Fra-2 transient expression into podocytes.This indicates that Fra-2 plays an important part in podocyte injury in LN. Baesd on the above, we postulate that Fra-2 decrease PPAR-γ levels and activity in injured podocytes and upgulate the TGF-β expression, which lead to the podocyte apoptosis. To confirm the hypothesis, we established podocytes injury model, by Fra-2 transient transfected into podocytes, and inbucated with PPAR-γ agonist observed the podocyte apoptosis. And, we obsereved these results in animal models and patients with LN.This study may demonstrate the molecular mechanism of Fra-2 in regulation of podocyte apoptosis, and provide a new target for treatmenting the LN.

狼疮性肾炎（LN）是系统性红斑狼疮最常见和最严重的继发性疾病，病情凶险，预后不良。近来，发现FOS样抗原2（Fra-2）与PPAR-γ启动子结合抑制其表达诱导脂肪细胞凋亡，又知PPAR-γ、TGF-β参与了足细胞凋亡，组织特异性Fra-2是否参与了LN足细胞损伤却不清楚。我们前期研究发现LN患者足细胞Fra-2表达水平显著高于其他肾脏疾病及对照，Fra-2瞬转足细胞系后，诱导了足细胞凋亡。因此我们推测Fra-2在足细胞通过抑制PPAR-γ表达进而提高TGF-β信号通路的活性，诱导足细胞凋亡，进而参与LN发生发展。为证实这一假说，我们利用培养的足细胞系，先通过瞬转Fra-2表达的质粒，模拟LN，并给予PPAR-γ激动剂，观察足细胞凋亡情况。同时，用狼疮小鼠以及LN患者肾组织验证体外实验取得的相关结果，从三个层面探讨Fra-2在LN足细胞凋亡中的重要作用，为LN的治疗提供新的药物靶点。

狼疮性肾炎（LN）是系统性红斑狼疮最常见和最严重的继发性疾病，病情凶险，预后不良。近来研究发现AP-1的亚基--FOS样抗原2（Fra-2）与PPAR-γ启动子结合抑制其表达诱导脂肪细胞凋亡，又知PPAR-γ、TGF-β参与了足细胞凋亡，组织特异性Fra-2是否参与了LN足细胞损伤却不清楚。我们前期研究发现LN患者足细胞Fra-2表达水平显著高于其他肾脏疾病及对照，Fra-2瞬转足细胞系后，诱导了足细胞凋亡。本项目结合以往文献及前期工作基础上，首次发现Fra-2表达于LN足细胞中，并通过体内及体外实验确定了Fra-2促进了LN足细胞凋亡。本实验发现在足细胞中PPAR-γ表达下调、TGF-β1表达上调，通过体内及体外实验进一步研究发现在LN足细胞中Fra-2通过与PPAR-γ结合抑制了PPAR-γ表达进而导致了TGF-β1的过表达，最终导致足细胞的凋亡，从而打破肾小球生理平衡，参与了LN的病理进程。本课题明确了Fra-2在LN发生发展中作用，Fra-2可以作为该疾病进程的一个生物学标志物，并为治疗该疾病的一个潜在药物靶标奠定理论基础。