作为影响微血管系统的糖尿病（DM）的一个突出并发症，糖尿病视网膜病变（DR）源于血视网膜屏障（BRB）损伤。据报道，天然多酚化合物绿原酸 (CGA) 可以缓解 DR。本研究深入探讨了 CGA 提供的抗 DR 保护作用的具体机制，并阐明了其在视网膜内皮细胞中的关键靶点。使用链脲佐菌素 (STZ) 诱导小鼠患糖尿病。 CGA 减轻了 BRB 功能障碍、白细胞粘附和体内无细胞血管的形成。 CGA 通过抑制核因子 kappa-B (NFκB) 抑制视网膜炎症和肿瘤坏死因子-α (TNFα) 的释放。此外，CGA 还降低了 TNFα 引发的外周血单核细胞 (PBMC) 与人视网膜内皮细胞 (HREC) 的粘附。 CGA 明显降低 TNFα 上调的血管细胞粘附分子 1 (VCAM1) 和细胞间粘附分子 1 (ICAM1) 的表达，并消除 TNFα 诱导的 HREC 中 NFκB 的激活。所有这些现象都可以通过在 HREC 中过度表达 1 型 TNF 受体 (TNFR1) 来逆转。在注射内皮特异性 TNFR1 过表达腺相关病毒 (AAV) 的小鼠中，CGA 对白细胞粘附和视网膜炎症的改善作用消失了。 CGA 通过与视网膜内皮细胞中的 TNFR1 结合，减少 TNFα 和 TNFR1 之间的相互作用。总之，除了通过抑制视网膜炎症来降低TNFα表达外，CGA还通过靶向视网膜内皮细胞中的TNFR1来阻断TNFα启动的NFκB激活，从而降低VCAM1和ICAM1表达，从而减少白细胞与视网膜血管的粘附。所有这些都减轻了视网膜炎症，最终减轻了 DR 中的 BRB 分解。版权所有 © 2024 Elsevier B.V. 保留所有权利。

As a prominent complication of diabetes mellitus (DM) affecting microvasculature, diabetic retinopathy (DR) originates from blood-retinal barrier (BRB) damage. Natural polyphenolic compound chlorogenic acid (CGA) has already been reported to alleviate DR. This study delves into the concrete mechanism of the CGA-supplied protection against DR and elucidates its key target in retinal endothelial cells. DM in mice was induced using streptozotocin (STZ). CGA mitigated BRB dysfunction, leukocytes adhesion and the formation of acellular vessels in vivo. CGA suppressed retinal inflammation and the release of tumor necrosis factor-α (TNFα) by inhibiting nuclear factor kappa-B (NFκB). Furthermore, CGA reduced the TNFα-initiated adhesion of peripheral blood mononuclear cell (PBMC) to human retinal endothelial cell (HREC). CGA obviously decreased the TNFα-upregulated expression of vascular cell adhesion molecule-1 (VCAM1) and intercellular adhesion molecule-1 (ICAM1), and abrogated the TNFα-induced NFκB activation in HRECs. All these phenomena were reversed by overexpressing type 1 TNF receptor (TNFR1) in HRECs. The CGA-provided improvement on leukocytes adhesion and retinal inflammation was disappeared in mice injected with an endothelial-specific TNFR1 overexpression adeno-associated virus (AAV). CGA reduced the interaction between TNFα and TNFR1 through binding to TNFR1 in retinal endothelial cells. In summary, excepting reducing TNFα expression via inhibiting retinal inflammation, CGA also reduced the adhesion of leukocytes to retinal vessels through decreasing VCAM1 and ICAM1 expression via blocking the TNFα-initiated NFκB activation by targeting TNFR1 in retinal endothelial cells. All of those mitigated retinal inflammation, ultimately alleviating BRB breakdown in DR.Copyright © 2024 Elsevier B.V. All rights reserved.