缺氧诱导因子1α与糖尿病并发症微循环学研究进展

Research progress on the microcirculation of HIF-1α and diabetic complications

组织和器官缺氧是微循环功能障碍的核心问题,也是糖尿病并发症发生的重要机制之一。靶器官微循环功能障碍导致的局部缺氧可能是DR、DKD、糖尿病周围神经病变和糖尿病性心肌病共同的病因学基础。缺氧诱导因子1α(HIF-1α)作为重要的核转录因子,具有氧浓度敏感性,通过调控下游功能基因表达水平,促进靶器官微血管内皮细胞增殖和微血管生成,对缺氧作出应答,从而参与糖尿病并发症的进程。HIF-1α及其信号通路抑制剂包括天然和化学合成小分子抑制剂两类,通过抑制HIF-1α表达、促进HIF-1α降解、影响HIF-1α在细胞核聚集、抑制HIF-1α与下游调控基因的结合等途径发挥HIF-1α抑制活性。筛选新的HIF-1α抑制剂可能成为治疗糖尿病并发症的新策略,具有一定的转化医学价值。

Tissues and organs hypoxia,occurred in microcirculation dysfunction,is one of the important mechanisms of diabetic complications.Organic hypoxia induced by microcirculatory dysfunction may be the common etiology of diabetic retinopathy,diabetic nephropathy,diabetic peripheral neuropathy and diabetic cardiomyopathy.Hypoxia-inducible factor-la(HIF-la)participates the progression of diabetes complications.As an important nuclear transcription factor with oxygen sensitivity,HIF-1αmaintains oxygen homeostasis,promotes microvascular endothelial cell proliferation and microvascular angiogenesis by regulating the expressions of downstream functional genes.Furthermore,HIF-1αand its signaling pathway inhibitorsincluding natural and chemical synthesized small molecules,could promote the degradation,affect the nuclear aggregation of HIF-la and interfere the combination between HIF-la and downstream genes.It may become a new strategy for the treatment of diabetic complications using novel HIF-la inhibitors,which carries translational medical values.