结缔组织生长因子诱导AGEs和氧化应激的不可逆变化参与糖尿病视网膜病变"代谢记忆"机制

Diabetic retinopathy, a serious microvascular complication of diabetes, is the leading cause of acquired blindness in young people. Many biochemical and molecular sequelae of hyperglycemia have been implicated in its pathogenesis. The progression of retinopathy resists arrest after hyperglycemia is terminated, suggesting a "metabolic memory" phenomenon in DR. However, the mechanism responsible for this "metabolic memory" remains unclear. Our recent studies have shown diabetes-induced alterations in retinal CTGF and apoptosis overexpression. The mechanism may be related with AGEs and oxidative stress. Recent studies suggest that some AGEs formation is an essentially phenomenon and could be responsible for the long-term nature of the metabolic memory. This study is to set up cell and animal models with different durations of poor and recover glycemic controls. We will examine the relationships of CTGF, apoptosis, angiogenesis, AGEs, and oxidative stress in the models. The relevance of CTGF and metabolic memory in DR will be investigate. We will demonstrate that CTGF induce the irreversible consequence of AGEs and oxidative stress and play an important role in the continued progression of diabetic retinopathy after hyperglycemia is terminated. It will be a future strategy consisting not only in an early aggressive treatment of hypergly-cemia, but with the simultaneous use of CTGF by siRNA reducing the deleterious metabolic memory effect of hyperglycemia on diabetic retinopathy.

糖尿病视网膜病变(DR)是糖尿病严重眼部并发症。当血糖控制较差一段时间再强化控制情况下仍会出现DR的进展，这就是DR的"代谢记忆"现象。我们前期对DR发病机制的系列研究发现，糖尿病视网膜内存在CTGF表达增高和细胞凋亡增强，其机制可能与晚期糖基化终末产物（AGEs）和氧化应激有关。另有研究显示部分AGEs在形成后不再逆转。本研究拟采用系列早期高血糖不同持续时间的细胞和动物模型，应用分子生物学等方法，观察视网膜细胞和组织中细胞凋亡和血管生成、CTGF、AGEs和氧化应激水平与早期高糖持续时间的关系，探讨CTGF与"代谢记忆"的相关性，及其通过诱导AGEs和氧化应激不可逆变化，促进DR发生发展的可能性；并通过siRNA技术抑制CTGF生成，探讨CTGF作为削弱"代谢记忆"视网膜损害靶点的可能性。本课题将探讨"代谢记忆"在DR发生发展中的作用机制与患者血糖控制方案结合，提供控制DR发生发展新思路

建立了高糖培养的视网膜内皮细胞模型和糖尿病大鼠模型；发现早期高糖持续时间与视网膜细胞和组织中CTGF、AGEs和氧化应激水平，细胞凋亡、视网膜血管生成具有明显相关性；进一步证明在糖尿病的视网膜细胞和组织内CTGF通过诱导AGEs和氧化应激持续作用，造成了不可逆转的分子损伤，调控视网膜细胞的增殖和凋亡、促进血管生成，参与高糖“代谢记忆”，最终促进了糖尿病视网膜病变的发生和进展。针对CTGF的治疗策略，减弱氧化应激和AGEs的作用，清除有害的代谢记忆，有望成为延缓糖尿病视网膜病变的治疗措施。