Insulin-like growth factor-I plays a pathogenetic role in diabetic retinopathy
Insulin-like growth factor-I plays a pathogenetic role in diabetic retinopathy
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DOI：
10.1016/s0002-9440(10)63311-1
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发表时间：
2004-08-01
影响因子：
6
通讯作者：
Adamis, AP
中科院分区：
文献类型：
--
作者：
Poulaki, V;Joussen, AM;Adamis, AP
糖尿病视网膜病变是西方世界失明的主要原因。异常的细胞间粘附分子-1的表达和白细胞粘附已被牵连在其发病机制，提高了潜在的慢性炎症机制的可能性。在目前的研究中，胰岛素样生长因子（IGF）-I在这些过程中的作用进行了研究。我们发现，用受体中和抗体或PI-3激酶（PI-3 K）、c-Jun激酶（JNK）或Akt抑制剂全身抑制IGF-I信号传导，可抑制视网膜Akt、JNK、HIF-1 α、核因子（NF）-κ B和AP-1活性、血管内皮生长因子（VEGF）表达以及细胞间粘附分子-1水平、白细胞停滞、和血视网膜屏障的破坏。玻璃体内注射IGF-I可增加视网膜Akt、JNK、HIF-1 α、NF-κ B和AP-1活性以及VEGF水平。IGF-I在体外刺激VEGF启动子活性，主要通过HIF-1 α，其次通过NF-κ B和AP-1。总之，IGF-I通过PI-3 K/Akt、HIF-1 α、NF-kappaB和继发性JNK/AP-1激活诱导视网膜VEGF表达，参与糖尿病视网膜病变的病理生理学。总之，这些体外和体内信号传导研究确定了药物干预的潜在靶点，以保护糖尿病患者的视力。
Diabetic retinopathy is a leading cause of blindness in the Western world. Aberrant intercellular adhesion molecule-1 expression and leukocyte adhesion have been implicated in its pathogenesis, raising the possibility of an underlying chronic inflammatory mechanism. In the current study, the role of insulin-like growth factor (IGF)-I in these processes was investigated. We found that systemic inhibition of IGF-I signaling with a receptor-neutralizing antibody, or with inhibitors of PI-3 kinase (PI-3K), c-Jun kinase (JNK), or Akt, suppressed retinal Akt, JNK, HIF-1alpha, nuclear factor (NF)-kappaB, and AP-1 activity, vascular endothelial growth factor (VEGF) expression, as well as intercellular adhesion molecule-1 levels, leukostasis, and blood-retinal barrier breakdown, in a relevant animal model. Intravitreous administration of IGF-I increased retinal Akt, JNK, HIF-1alpha, NF-kappaB, and AP-1 activity, and VEGF levels. IGF-I stimulated VEGF promoter activity in vitro, mainly via HIF-1alpha, and secondarily via NF-kappaB and AP-1. In conclusion, IGF-I participates in the pathophysiology of diabetic retinopathy by inducing retinal VEGF expression via PI-3K/Akt, HIF-1alpha, NF-kappaB, and secondarily, JNK/AP-1 activation. Taken together, these in vitro and in vivo signaling studies thus identify potential targets for pharmacological intervention to preserve vision in patients with diabetes.