活性维生素D3调控糖尿病肾病巨噬细胞M1/M2型活化机制研究

Macrophage activation is a key point in the progression of diabetic nephropathy (DN). Increasing evidences suggest that the heterogeneity of macrophage phenotype and function ultimately determines the outcome of DN. Classically activated macrophages (M1) contribute to tissue inflammation and fibrosis, while alternatively activated macrophages (M2) mediate tissue repair. Recent studies demonstrate that active vitamin D3 (aVitD3) has potential renal protective effects, significantly ameliorates renal dysfunction and fibrotic lesions in patients of DN, although the mechanism remains unclear. Our previous studies have shown that aVitD3 can promote the switching of M1 macrophage to M2 ones and consequently inhibits podocyte injury and glomerular impairement and protects renal function. Activation of macrophage is related with STATs signaling and aVitD3 plays biological effects via vitamin D receptor, whereas if there is Cross-Talk between above two factors has not been elucidated. The current study is aimed to investigate the molecular mechanism of aVitD3 regulation of macrophage M1/M2 activation in diabetic nephropathy and related intracellular signaling pathway. Whole study is divided into three aspects including clinical research, animal study and cell culture. The resulte of the study is expected to find novel information regarding the therapeutic target point of diabetic nephropathy.

巨噬细胞活化是糖尿病肾病（DN）早期的重要环节。巨噬细胞活化状态和功能的两面性决定肾脏疾病的不同转归。巨噬细胞经典M1型活化介导炎症反应与纤维化，替代途径M2型活化具有组织修复作用。近期临床研究发现，活性维生素D3对DN具有显著的肾保护作用。我们前期研究发现，活性维生素D3能阻断高糖诱导的巨噬细胞M1型活化并使其向M2型转化，进而保护足细胞。巨噬细胞活化与STATs活化有关，维生素D3通过维生素D受体发挥作用，然而这两者之间是否通过Cross-Talk来调节巨噬细胞活化，值得深入研究。本研究拟在前期工作基础上，通过临床研究（DN患者肾脏病理研究）、动物实验（DN大鼠模型）和细胞培养（巨噬细胞活化调节及基因敲除技术）三个不同层次，试图首次阐明活性维生素D3调节巨噬细胞M1/M2型活化平衡的分子机制及细胞内信号转导途径，从而为找到活性维生素D3早期防治糖尿病肾病关键靶点提供新的线索和理论依据。

巨噬细胞活化是糖尿病肾病（DN）早期的重要环节。巨噬细胞活化状态和功能的两面性决定肾脏疾病的不同转归。巨噬细胞经典M1型活化介导炎症反应与纤维化，替代途径M2型活化具有组织修复作用。近期临床研究发现，活性维生素D3对DN具有显著的肾保护作用。本研究在前期工作基础上，通过临床研究（DN患者肾脏病理研究）、动物实验（DN大鼠模型）和细胞培养（巨噬细胞活化调节及基因敲除技术）三个不同层次，首次阐明活性维生素D3调节巨噬细胞M1/M2型活化平衡的分子机制及细胞内信号转导途径，发现活性维生素D3不仅能够通过STAT-1-TREM-1途径调节巨噬细胞表型转化，还能通过下调TREM-1表达抑制巨噬细胞的粘附迁移功能进而降低巨噬细胞的浸润。此外，我们进一步探究了自噬在巨噬细胞表型转化中的作用及巨噬细胞在钙化防御血管微钙化形成中的作用及机制，为找到活性维生素D3早期防治糖尿病肾病关键靶点提供新的线索和理论依据。