ANGPTL-4/Profilin-1通路在糖尿病视网膜病变代谢记忆分子机制中的作用

糖尿病视网膜病变（DR）是工作年龄人群中首位致盲性病变，高血糖独特的“代谢记忆”效应造成DR患者在血糖控制正常稳定后，病情仍持续进展，故研究其具体机制非常必要。申请人前期研究发现，ANGPTL-4和Profilin-1在DR高糖环境中均高表达且具有相关性，ANGPTL-4与血脂和VEGF关系密切，而Profilin-1在DR血管炎性病变等过程中发挥重要作用；但ANGPTL-4对Profilin-1的具体调控机制尚不明确。为阐明其机制，我们利用高糖代谢记忆细胞和动物模型，验证高糖活化ANGPTL-4，进而上调Profilin-1，可能通过激活细胞凋亡、炎症及血管生成因子通路，最终引起视网膜血管炎性损伤；并进行体内干预，检测ANGPTL-4/Profilin-1通路是否为DR治疗的有效靶点。本课题有望阐明ANGPTL-4/Profilin-1通路在代谢记忆中的作用，为DR的临床防治提供新思路。

Diabetic retinopathy (DR) is the primary leading cause of blindness in working-age people. The effect of metabolic memory of hyperglycemia, which not only affects the pathogenesis but also the therapeutic effect and prognosis of DR, prolongs DR progression after good control of hyperglycemia. Hitherto, relative research focusing on metabolic memory effect is still at its preliminary stage. Recently, we have provided proofs that the expression levels of angiopoietin-like protein 4 (ANGPTL-4), a novel adipocytokine, and profilin-1, are both significantly elevated and correlated under high glucose (HG) conditions of DR; furthers, ANGPTL-4 correlates with serum lipids and vascular endothelial growth factor, and profilin-1 mediates critical pathology of DR, such as inflammation, apoptosis and angiogenesis, etc. However, the mechanism of ANGPTL-4 affects profilin-1 remains unknown. To clarify this, we adopt in vivo and in vitro models of hyperglycemia metabolic memory to demonstrate that HG-activated ANGPTL-4 mediates inflammation, apoptosis and angiogenesis via up-regulating profilin-1, favoring DR vascular inflammatory dysfunction progression. Then, we reveal the therapy-targeting role of ANGPTL-4/profilin-1 pathway for DR via small interfering RNA. The prospection of this research would help elucidate the role of ANGPTL-4/profilin-1 pathway in DR metabolic memory and provide new thoughts for clinical prevention and therapy of DR.