Aryl hydrocarbon receptor deficiency augments dysregulated microangiogenesis and diabetic retinopathy

Wen-Jane Lee; Keng-Hung Lin; Jun-Sing Wang; Wayne Huey-Herng Sheu; Chin-Chang Shen; Cheng-Ning Yang; Sheng-Mao Wu; Li-Wei Shen; Shu-Hua Lee; De-Wei Lai; Keng-Li Lan; Chun-Wei Tung; Shing-Hwa Liu; Meei-Ling Sheu

Biomedicine & Pharmacotherapy (Nov 2022)

Aryl hydrocarbon receptor deficiency augments dysregulated microangiogenesis and diabetic retinopathy

Wen-Jane Lee,
Keng-Hung Lin,
Jun-Sing Wang,
Wayne Huey-Herng Sheu,
Chin-Chang Shen,
Cheng-Ning Yang,
Sheng-Mao Wu,
Li-Wei Shen,
Shu-Hua Lee,
De-Wei Lai,
Keng-Li Lan,
Chun-Wei Tung,
Shing-Hwa Liu,
Meei-Ling Sheu

Affiliations

Wen-Jane Lee: Department of Medical Research, Taichung Veterans General Hospital, Taiwan
Keng-Hung Lin: Department of Ophthalmology, Taichung Veterans General Hospital, Taiwan; Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan
Jun-Sing Wang: Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan; Division of Endocrinology and Metabolism, Taichung Veterans General Hospital, Taiwan; Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan
Wayne Huey-Herng Sheu: Division of Endocrinology and Metabolism, Department of Internal Medicine, Taipei Veterans General Hospital, Taiwan
Chin-Chang Shen: Institute of Nuclear Energy Research, Atomic Energy Council, Taoyuan, Taiwan
Cheng-Ning Yang: Department of Dentistry, School of Dentistry, College of Medicine, National Taiwan University, Taipei, Taiwan
Sheng-Mao Wu: Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan
Li-Wei Shen: Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan
Shu-Hua Lee: Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan
De-Wei Lai: Experimental Animal Center, Department of Molecular Biology and Cell Research, Chang Bing Show Chwan Memorial Hospital, Changhua, Taiwan
Keng-Li Lan: Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan; Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan
Chun-Wei Tung: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Taiwan
Shing-Hwa Liu: Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan
Meei-Ling Sheu: Department of Medical Research, Taichung Veterans General Hospital, Taiwan; Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan; Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan; Correspondence to: Institute of Biomedical Sciences, College of Life Sciences, National Chung Hsing University, 250, Kuo Kuang Road, Taichung 402, Taiwan.

Journal volume & issue: Vol. 155
p. 113725

Abstract

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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.

Published in Biomedicine & Pharmacotherapy

ISSN: 0753-3322 (Print); 1950-6007 (Online)
Publisher: Elsevier
Country of publisher: France
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: https://www.journals.elsevier.com/biomedicine-and-pharmacotherapy

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