Rationale: Diabetic retinopathy is characterized by vasopermeability, vascular leakage, inflammation, blood–retinal barrier breakdown, capillary degeneration, and neovascularization. However, the mechanisms underlying the association between diabetes mellitus and progression retinopathy remain unclear.

Objective: TPL2 (tumor progression locus 2), a serine-threonine protein kinase, exerts a pathological effect on vascular angiogenesis. This study investigated the role of N^ε-(carboxymethyl)lysine, a major advanced glycation end products, and the involved TPL2-related molecular signals in diabetic retinopathy using models of in vitro and in vivo and human samples.

Methods and Results: Serum N^ε-(carboxymethyl)lysine levels and TPL2 kinase activity were significantly increased in clinical patients and experimental animals with diabetic retinopathy. Intravitreal administration of pharmacological blocker or neutralizing antibody inhibited TPL2 and effectively suppressed the pathological characteristics of retinopathy in streptozotocin-induced diabetic animal models. Intravitreal VEGF (vascular endothelial growth factor) neutralization also suppressed the diabetic retinopathy in diabetic animal models. Mechanistic studies in primary human umbilical vein endothelial cells and primary retinal microvascular endothelial cells from streptozotocin-diabetic rats, db/db mice, and samples from patients with diabetic retinopathy revealed a positive parallel correlation between N^ε-(carboxymethyl)lysine and the TPL2/chemokine SDF1α (stromal cell–derived factor-α) axis that is dependent on endoplasmic reticulum stress-related molecules, especially ATF4 (activating transcription factor-4).

Conclusions: This study demonstrates that inhibiting the N^ε-(carboxymethyl)lysine-induced TPL2/ATF4/SDF1α axis can effectively prevent diabetes mellitus–mediated retinal microvascular dysfunction. This signaling axis may include the therapeutic potential for other diseases involving pathological neovascularization or macular edema.

理由：糖尿病性视网膜病的特征是血管通透性，血管渗漏，炎症，血视网膜屏障破坏，毛细血管变性和新血管形成。然而，糖尿病与进展性视网膜病之间的关联的潜在机制尚不清楚。

目的：丝氨酸-苏氨酸蛋白激酶TPL2（肿瘤进展位点2）对血管新生具有病理作用。本研究调查N中的作用^ε - （羧甲基）赖氨酸，一个主要的晚期糖化终产物，并且在糖尿病性视网膜病，使用体外和体内和人类样品模型所涉及的TPL2相关分子信号。

方法和结果：血清^Nε在糖尿病性视网膜病的临床患者和实验动物中，-（羧甲基）赖氨酸水平和TPL2激酶活性显着增加。在链脲佐菌素诱导的糖尿病动物模型中，玻璃体内给药药理阻断剂或中和抗体可抑制TPL2并有效抑制视网膜病变的病理特征。玻璃体内VEGF（血管内皮生长因子）的中和作用还抑制了糖尿病动物模型中的糖尿病视网膜病变。在原代人类机理研究脐静脉内皮从链脲霉素糖尿病大鼠，db / db小鼠，和样品来自患有糖尿病性视网膜病的细胞和原发性视网膜微血管内皮细胞揭示N之间的正并行相关^ε-（羧甲基）赖氨酸和TPL2 /趋化因子SDF1α（基质细胞衍生因子-α）轴，该轴依赖于内质网应激相关分子，尤其是ATF4（激活转录因子4）。

结论：本研究表明抑制Ñ ^ε - （羧甲基）赖氨酸诱导TPL2 / ATF4 /SDF1α轴可以有效地防止糖尿病介导的视网膜微血管功能障碍。该信号转导轴可包括对其他涉及病理性新血管形成或黄斑水肿的疾病的治疗潜力。