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

doi:10.1016/j.biopha.2022.113725

Aryl hydrocarbon receptor deficiency augments dysregulated microangiogenesis and diabetic retinopathy

Biomed Pharmacother. 2022 Nov:155:113725. doi: 10.1016/j.biopha.2022.113725. Epub 2022 Sep 21.

Authors

Wen-Jane Lee¹, Keng-Hung Lin², Jun-Sing Wang³, Wayne Huey-Herng Sheu⁴, Chin-Chang Shen⁵, Cheng-Ning Yang⁶, Sheng-Mao Wu⁷, Li-Wei Shen⁷, Shu-Hua Lee⁷, De-Wei Lai⁸, Keng-Li Lan⁹, Chun-Wei Tung¹⁰, Shing-Hwa Liu¹¹, Meei-Ling Sheu¹²

Affiliations

¹ Department of Medical Research, Taichung Veterans General Hospital, Taiwan.
² Department of Ophthalmology, Taichung Veterans General Hospital, Taiwan; Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan.
³ 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.
⁴ Division of Endocrinology and Metabolism, Department of Internal Medicine, Taipei Veterans General Hospital, Taiwan.
⁵ Institute of Nuclear Energy Research, Atomic Energy Council, Taoyuan, Taiwan.
⁶ Department of Dentistry, School of Dentistry, College of Medicine, National Taiwan University, Taipei, Taiwan.
⁷ Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan.
⁸ Experimental Animal Center, Department of Molecular Biology and Cell Research, Chang Bing Show Chwan Memorial Hospital, Changhua, Taiwan.
⁹ Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan; Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.
¹⁰ Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Taiwan.
¹¹ Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan.
¹² 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. Electronic address: mlsheu@nchu.edu.tw.

PMID: 36152407
DOI: 10.1016/j.biopha.2022.113725

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.

Keywords: Aryl hydrocarbon receptor; Diabetic retinopathy; Inflammasome; Pigment epithelium-derived factor.

MeSH terms

Animals
Diabetes Mellitus* / metabolism
Diabetic Retinopathy* / drug therapy
Endothelial Cells / metabolism
Humans
Inflammasomes / metabolism
Mice
Mice, Inbred C57BL
Molecular Docking Simulation
Receptors, Aryl Hydrocarbon / genetics
Receptors, Aryl Hydrocarbon / metabolism
Retina
Streptozocin / pharmacology
Xenobiotics / metabolism

Substances

Receptors, Aryl Hydrocarbon
Streptozocin
Inflammasomes
Xenobiotics