From the Institute of Biomedical Sciences (D.-W.L., M.-L.S.), Department of Chemistry (M.-R.L., C.-Y.C.), Rong Hsing Research Center for Translational Medicine (K.-H.L., W.H.-H.S., M.-L.S.), National Chung Hsing University, Taichung, Taiwan; Department of Ophthalmology (K.-H.L.), Division of Endocrinology and Metabolism (W.H.-H.S.), and Department of Medical Research (W.-J.L., Y.-W.H., M.-L.S.), Taichung Veterans General Hospital, Taiwan; Institute of Nuclear Energy Research, Atomic Energy Council, Taoyuan, Taiwan (C.-C.S.); Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan (T.-J.C.); Department of Internal Medicine, Armed Forces Taichung General Hospital, Taiwan (T.-J.C.); Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan (S.-H.L.); and Institute of Toxicology, College of Medicine, National Taiwan University, Taipei (S.-H.L.).
Circ Res. 2017 Sep 1;121(6):e37-e52. doi: 10.1161/CIRCRESAHA.117.311066. Epub 2017 Jul 19.
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.
TPL2 (tumor progression locus 2), a serine-threonine protein kinase, exerts a pathological effect on vascular angiogenesis. This study investigated the role of N-(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.
Serum N-(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-(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).
This study demonstrates that inhibiting the N-(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.
糖尿病性视网膜病变的特征是血管通透性、血管渗漏、炎症、血视网膜屏障破坏、毛细血管退化和新生血管形成。然而，糖尿病与视网膜病变进展之间的关联机制尚不清楚。
TPL2（肿瘤进展基因座 2）是一种丝氨酸-苏氨酸蛋白激酶，对血管血管生成具有病理作用。本研究使用体外和体内模型以及人类样本，研究了糖尿病性视网膜病变中主要的晚期糖基化终产物 N-（羧甲基）赖氨酸和涉及的 TPL2 相关分子信号的作用。
临床患者和实验性糖尿病性视网膜病变动物的血清 N-（羧甲基）赖氨酸水平和 TPL2 激酶活性均显著升高。药理抑制剂或中和抗体的玻璃体内给药抑制 TPL2，并有效抑制链脲佐菌素诱导的糖尿病动物模型中的视网膜病变病理特征。玻璃体内 VEGF（血管内皮生长因子）中和也抑制了糖尿病动物模型中的糖尿病性视网膜病变。在原代人脐静脉内皮细胞和链脲佐菌素诱导的糖尿病大鼠、db/db 小鼠的原代视网膜微血管内皮细胞以及来自糖尿病性视网膜病变患者的样本中的机制研究表明，N-（羧甲基）赖氨酸与 TPL2/趋化因子 SDF1α（基质细胞衍生因子-α）轴之间存在正平行相关性，该轴依赖于内质网应激相关分子，特别是 ATF4（激活转录因子 4）。
本研究表明，抑制 N-（羧甲基）赖氨酸诱导的 TPL2/ATF4/SDF1α 轴可有效预防糖尿病介导的视网膜微血管功能障碍。该信号轴可能包括涉及病理性新生血管形成或黄斑水肿的其他疾病的治疗潜力。
