活性维生素D3上调自噬活性防治糖尿病肾病足细胞损伤及机制研究

Podocyte injury plays a critical role in the development and progress of diabetic nephropathy (DN). Recent studies have focused on that autophagy plays a key role in maintaining intracellular of podocyte homeostasis in DN. 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 reduce proteinuria, inhibit podocyte injury and glomerular impairment and protect renal function. However, studies have yet to address whether aVitD3 alleviates diabetic nephropathy and podocyte injury, through the upregulation autophagy activity. In this study, we aimed to elucidate whether the effects of aVitD3 via recovering of autophagic function ameliorates podocyte injury in DN. aVitD3 induced autophagy is mediated partly through VDR-PI3K/p-Akt signaling pathway. Whole study is divided into two aspects including animal study and cell culture. The result of the study is expected to find novel information regarding the therapeutic target point of aVitD3 in diabetic nephropathy.

足细胞损伤是糖尿病肾病（DN）早期的重要环节。研究证实，自噬在DN足细胞稳态发挥着关键作用。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能显著降低DN大鼠蛋白尿水平，减轻DN大鼠足细胞损伤，其机制是通过调节PI3K/p-Akt信号通路实现的。然而，活性维生素D3是否通过上调自噬活性减轻糖尿病肾病足细胞损伤，其机制如何，至今尚无相关报道，有待深入探讨。本研究拟在前期工作基础上，通过动物实验和细胞培养，试图阐明活性维生素D3通过上调自噬活性减轻糖尿病肾病足细胞损伤，延缓糖尿病肾病的发生与发展，探讨VDR-PI3K-Akt信号通路可能是活性维生素D3上调自噬活性的重要分子机制。这将为活性维生素D3防治糖尿病肾病足细胞损伤寻找作用靶点提供理论依据。

糖尿病肾病（diabetic nephropathy，DN）是糖尿病的严重微血管并发症之一。近年来大量研究表明，足细胞损伤是DN发生发展的核心环节。我们及其他学者前期研究证实足细胞表型及相关分子表达的异常是DN早期受损的重要标志。然而，DM时足细胞损伤的具体机制目前尚未阐明。最新研究提示，足细胞自噬活性的降低是DN足细胞损伤的关键因素。多个研究已经证实，自噬对于改善糖尿病肾病足细胞损伤至关重要。因此，寻找有效的上调足细胞自噬的药物是防治DN足细胞损伤的关键。通过本项目的研究发现：（1）活性维生素D3通过上调自噬活性减轻糖尿病肾病足细胞损伤；（2）VDR可能是活性维生素D3上调自噬活性的重要分子机制。这将为活性维生素D3防治糖尿病肾病足细胞损伤寻找作用靶点提供理论依据。