基于“肝目轴”对桃红四物汤中芍药苷通过调节HIF-1α通路改善糖尿病视网膜病变微循环障碍的机制研究

糖尿病视网膜病变DR是糖尿病主要慢性微血管并发症之一，也是导致视力下降及失明的主要原因之一。桃红四物汤是活血化瘀经典名方，用于DR治疗已取得良好疗效，但机制不清。前期发现，芍药苷是桃红四物汤关键有效成分之一，与HIF-1α通路中多个重要靶点作用；芍药苷抑制高糖诱导的视网膜微血管内皮细胞侵袭、迁移和血管生成能力、抑制其HIF-1α和VEGF表达，也提高胰岛素抵抗肝细胞葡萄糖消耗量和糖原含量、抑制其HIF-1α表达。由此提出假说，芍药苷从“肝目轴”角度影响DR疾病进程，涉及机制可能为，调节HIF-1α信号通路改善DR微循环障碍，包括改善视网膜细胞病理状态和肝细胞胰岛素抵抗。本项目拟通过动物实验、细胞分子生物学实验、基因干扰/过表达实验等，从“肝目轴”角度考察芍药苷在DR作用，阐述其通过HIF-1α通路改善DR微循环障碍的作用机制，为DR临床治疗提供候选药物，也为DR基础和临床研究提供新思路。

Diabetic retinopathy (DR) is one of the major chronic microvascular complications of diabetes mellitus and one of the main causes of vision loss and blindness. Taohong Siwu decoction is a classic prescription for promoting blood circulation and removing blood stasis. It has achieved good efficacy in the treatment of DR, but the mechanism is not clear. It was previously found that paeoniflorin was one of the key active components of Taohong Siwu decoction and could act on several important targets in the HIF-1α pathway. In addition, paeoniflorin could inhibit the invasion, migration and angiogenesis in retinal microvascular endothelial cells induced by high glucose, and down-regulate the expression of HIF-1α and VEGF. Paeoniflorin could also increase the glucose consumption and glycogen content in insulin resistant liver cells, and down-regulate the expression of HIF-1α. Therefore, it was proposed that paeoniflorin could affect the progression of DR from the perspective of "liver-eye axis", and the mechanisms might be involved in regulating the HIF-1α signaling pathway to improve the microcirculation disorder of DR, including improving the pathological state of retinal cells and the insulin resistance of hepatocytes. Using animal experiments, cellular and molecular biology experiments, gene interference or over-expression experiments and so on, this study aims to verify the effects of paeoniflorin on DR and explore the mechanisms of paeoniflorin alleviating microcirculatory disturbance of DR by regulating HIF-1α signaling pathway from the perspective of "liver-eye axis". This study will provide candidate drugs for DR clinical treatment, and also provide new ideas for DR basic and clinical research.