Diabetic retinopathy (DR) is a pathophysiologic vasculopathic process with obscure mechanisms and limited effective therapeutic strategies. Aryl hydrocarbon receptor (AhR) is an important regulator of xenobiotic metabolism and an environmental sensor. The aim of the present study was to investigate the role of AhR in the development of DR and elucidate the molecular mechanism of its downregulation. DR was evaluated in diabetes-induced retinal injury in wild type and AhR knockout (AhR-/-) mice. Retinal expression of AhR was determined in human donor and mice eyes by immunofluorescence since AhR activity was examined in diabetes. AhR knockout (AhRKO) mice were used to induce diabetes with streptozotocin, high-fat diet, or genetic double knockout with diabetes spontaneous mutation (Leprdb) (DKO; AhR-/-×Leprdb/db) for investigating structural, functional, and metabolic abnormalities in vascular and epithelial retina. Structural molecular docking simulation was used to survey the pharmacologic AhR agonists targeting phosphorylated AhR (Tyr245). Compared to diabetic control mice, diabetic AhRKO mice had aggravated alterations in retinal vasculature that amplified hallmark features of DR like vasopermeability, vascular leakage, inflammation, blood-retinal barrier breakdown, capillary degeneration, and neovascularization. AhR agonists effectively inhibited inflammasome formation and promoted AhR activity in human retinal microvascular endothelial cells and pigment epithelial cells. AhR activity and protein expression was downregulated, resulting in a decrease in DNA promoter binding site of pigment epithelium-derived factor (PEDF) by gene regulation in transcriptional cascade. This was reversed by AhR agonists. Our study identified a novel of DR model that target the protective AhR/PEDF axis can potentially maintain retinal vascular homeostasis, providing opportunities to delay the development of DR.

糖尿病视网膜病变 (DR) 是一种病理生理性血管病变过程，其机制不明，有效的治疗策略有限。芳烃受体 (AhR) 是外源代谢的重要调节剂和环境传感器。本研究的目的是研究 AhR 在 DR 发展中的作用，并阐明其下调的分子机制。在野生型和 AhR 敲除 (AhR-/-) 小鼠中评估了糖尿病引起的视网膜损伤中的 DR。由于在糖尿病中检测了 AhR 活性，因此通过免疫荧光在人类供体和小鼠眼睛中确定了 AhR 的视网膜表达。AhR 敲除 (AhRKO) 小鼠用于用链脲佐菌素、高脂肪饮食或糖尿病自发突变 (Leprdb) (DKO; AhR-/-×Leprdb/db) 的基因双敲除诱导糖尿病，以研究结构、血管和上皮视网膜的功能和代谢异常。结构分子对接模拟用于研究靶向磷酸化 AhR (Tyr245) 的药理学 AhR 激动剂。与糖尿病对照小鼠相比，糖尿病 AhRKO 小鼠的视网膜脉管系统发生了严重的改变，从而放大了 DR 的标志性特征，如血管通透性、血管渗漏、炎症、血视网膜屏障破坏、毛细血管变性和新生血管形成。AhR 激动剂有效抑制炎症小体的形成并促进人视网膜微血管内皮细胞和色素上皮细胞中的 AhR 活性。AhR 活性和蛋白质表达下调，通过转录级联中的基因调控导致色素上皮衍生因子 (PEDF) 的 DNA 启动子结合位点减少。这被 AhR 激动剂逆转。我们的研究确定了一种针对保护性 AhR/PEDF 轴的新型 DR 模型，可以潜在地维持视网膜血管稳态，为延缓 DR 的发展提供机会。