Aryl hydrocarbon receptor deficiency augments dysregulated microangiogenesis and diabetic retinopathy
Journal
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
Journal Volume
155
Date Issued
2022-11
Author(s)
Lee, Wen-Jane
Lin, Keng-Hung
Wang, Jun-Sing
Sheu, Wayne Huey-Herng
Shen, Chin-Chang
Yang, Cheng-Ning
Wu, Sheng-Mao
Shen, Li-Wei
Lee, Shu-Hua
Lai, De-Wei
Lan, Keng-Li
Tung, Chun-Wei
Sheu, Meei-Ling
Abstract
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.
Subjects
Aryl hydrocarbon receptor; Diabetic retinopathy; Inflammasome; Pigment epithelium-derived factor
SDGs
Publisher
Elsevier Masson s.r.l.
Type
journal article