TAM受体酪氨酸激酶介导的PI3K/AKT信号通路在狼疮性肾炎发病中的作用机制

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by generation of autoantibodies particularly against components in the cell nucleus. Lupus nephritis (LN) is one of the most serious complications of SLE and is associated with high rates of morbidity and mortality. The tyro 3, axl, mer(TAM) receptor tyrosine kinase play an especially important role in the autoimmune disease. There are no studies that the TAM receptor tyrosine kinase control the abnormal activation of human antoreactive B cells and induce the incidence of LN. The PI3K/AKT pathway is a multiple functional signal pathway that involved in cell proliferation, differentiation,motility and lipid metabolism. Serine-threonine protein kinase AKT ( also know n as protein kinase B) is a major downstream target of PI3K for regulating tumor growth and angiogenesis. PTEN is a dual-specificity phosphatase which has protein phosphatase activity and lipid phosphatase activity that antagonizes PI3K activity. PTEN negatively regulates the activity of PI3K/AKT signaling through converting phosphatidyli-nositol 3,4,5-triphosphate(PIP3) into phosphatidylinositol 4,5-bisphosphate(PIP2). The PI3K/AKT pathway plays the important role with the activation of human antoreactive B cells in SLE. However，it has not been reported that TAM receptor tyrosine kinase control the activation of human antoreactive B cells through the PI3K/AKT pathway and induce the incidence of LN. Therefore, to determine regulate PI3K/AKT signaling pathway and if this has whether the TAM receptor tyrosine kinase can effects lupus nephritis.Accordingly, PI3K/AKT pathway inhibitors are likely more effective in patients with active PI3K/AKT signaling in case such as PTEN mutations. The therapeutic methods targeting PI3K/AKT pathway would represent the promising lupus nephritis therapy in the future.

狼疮性肾炎是系统性红斑狼疮最常见也是最严重的临床病症之一，约有12%的患者走向终末期肾病，死亡率居高不下，因此狼疮性肾炎的防治是至关重要的。研究表明：B淋巴细胞PI3K/AKT信号通路的异常活化与系统性红斑狼疮自身免疫的发生发展密切相关。本项目以PI3K/AKT信号通路为切入点，运用分子生物学方法探讨TAM受体酪氨酸激酶及其配体与狼疮性肾炎活动性及肾脏损害的相关性，应用体外实验阐明AKT、PTEN在狼疮性肾炎外周血B细胞的的表达特点及TAM受体对狼疮性肾炎患者B细胞AKT、PTEN的活化作用是否存在调控作用，采用动物实验探讨.PI3Kgamma抑制剂对MRL/lpr狼疮小鼠的肾保护作用及机制。本研究不仅为今后诊断狼疮性肾炎提供无创的可靠指标，而且为我国狼疮性肾炎防治的可持续研究提供相关科学依据。因此，如果本实验成功完成，对于狼疮性肾炎患者延缓肾脏病变、减少终末期肾病的发病率具有很重要的意义。

近年研究表明，TAM 受体酪氨酸激酶亚家族（TYRO3、MER 和AXL）在自身免疫性疾病的发病过程中起着重要的作用。B淋巴细胞PI3K/AKT信号通路的异常活化与系统性红斑狼疮自身免疫的发生发展密切相关。本项目以PI3K/AKT信号通路为切入点，运用分子生物学方法探讨TAM体酪氨酸激酶及其配体与狼疮性肾炎活动性及肾脏损害的相关性，应用体外实验阐明AKT、PTEN在狼疮性肾炎外周血B细胞的的表达特点及TAM受体对狼疮性肾炎患者B细胞AKT、PTEN的活化作用是否存在调控作用。结果如下：⑴LN患者血浆MER、sAXL及Gas6的表达水平明显高于SLE患者。在LN患者中，血浆MER、sAXL及Gas6的表达水平与肾功能、肾脏病理活动指数等明显相关。因此，血浆MER、sAXL及Gas6的表达水平可作为判断LN患者疾病严重程度、肾脏损害程度的参考指标。⑵外周血AKT及PTEN mRNA及蛋白质的表达水平可作为判断LN患者疾病严重程度、肾脏损害程度的参考指标。外周血AKT及PTEN mRNA及蛋白质的表达水平与血浆MER、sAXL及Gas6的表达水平具有相关性。因此，狼疮性肾炎患者中TAM受体酪氨酸激酶对B细胞的异常活化作用可能是通过PI3K/AKT信号通路进行调整的并参与狼疮性肾炎的发病过程。⑶通过体外实验进一步证实了TAM受体酪氨酸激酶(MER、AXL)是通过激活PI3K/AKT信号通路调整B细胞的异常活化并参与狼疮性肾炎的发病机制，PI3K抑制剂LY294002抑制剂明显抑制其活化作用，为LN的治疗提供新的靶点。本研究不仅为今后诊断狼疮性肾炎提供无创的可靠指标，对于狼疮性肾炎患者延缓肾脏病变、减少终末期肾病的发病率具有很重要的意义。