Aryl hydrocarbon receptor deficiency causes dysregulated cellular matrix metabolism and age-related macular degeneration-like pathology

Peng Hu, Rolf Herrmann, Amanda Bednar, Peter Saloupis, Mary A. Dwyer, Ping Yang, Xiaoping Qi, Russell S. Thomas, Glenn J. Jaffe, Michael E. Boulton, Donald P. McDonnell, Goldis Malek

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

The aryl hydrocarbon receptor (AhR) is a nuclear receptor that regulates xenobiotic metabolism and detoxification. Herein, we report a previously undescribed role for the AhR signaling pathway as an essential defense mechanism in the pathogenesis of early dry age-related macular degeneration (AMD), the leading cause of vision loss in the elderly. We found that AhR activity and protein levels in human retinal pigment epithelial (RPE) cells, cells vulnerable in AMD, decrease with age. This finding is significant given that age is the most established risk factor for development of AMD. Moreover, AhR-/- mice exhibit decreased visual function and develop dry AMD-like pathology, including disrupted RPE cell tight junctions, accumulation of RPE cell lipofuscin, basal laminar and linear-like deposit material, Bruch's membrane thickening, and progressive RPE and choroidal atrophy. High-serum low-density lipoprotein levels were also observed in AhR-/- mice. In its oxidized form, this lipoprotein can stimulate increased secretion of extracellular matrix molecules commonly found in deposits from RPE cells, in an AhR-dependent manner. This study demonstrates the importance of cellular clearance via the AhR signaling pathway in dry AMD pathogenesis, implicating AhR as a potential target, and the mouse model as a useful platform for validating future therapies.

Original languageEnglish (US)
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number43
DOIs
StatePublished - Oct 22 2013
Externally publishedYes

Fingerprint

Aryl Hydrocarbon Receptors
Macular Degeneration
Retinal Pigments
Pathology
Epithelial Cells
Bruch Membrane
Lipofuscin
Intercellular Junctions
Tight Junctions
Xenobiotics
Defense Mechanisms
Cytoplasmic and Nuclear Receptors
LDL Lipoproteins
Lipoproteins
Atrophy
Extracellular Matrix
Serum
Proteins

Keywords

  • Oxidized low density lipoprotein
  • Retinal disease
  • Retinal pigment epithelium
  • Toxin metabolism

ASJC Scopus subject areas

  • General

Cite this

Aryl hydrocarbon receptor deficiency causes dysregulated cellular matrix metabolism and age-related macular degeneration-like pathology. / Hu, Peng; Herrmann, Rolf; Bednar, Amanda; Saloupis, Peter; Dwyer, Mary A.; Yang, Ping; Qi, Xiaoping; Thomas, Russell S.; Jaffe, Glenn J.; Boulton, Michael E.; McDonnell, Donald P.; Malek, Goldis.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 110, No. 43, 22.10.2013.

Research output: Contribution to journalArticle

Hu, Peng ; Herrmann, Rolf ; Bednar, Amanda ; Saloupis, Peter ; Dwyer, Mary A. ; Yang, Ping ; Qi, Xiaoping ; Thomas, Russell S. ; Jaffe, Glenn J. ; Boulton, Michael E. ; McDonnell, Donald P. ; Malek, Goldis. / Aryl hydrocarbon receptor deficiency causes dysregulated cellular matrix metabolism and age-related macular degeneration-like pathology. In: Proceedings of the National Academy of Sciences of the United States of America. 2013 ; Vol. 110, No. 43.
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