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Sci Rep. 2017 Nov 23;7(1):16168. doi: 10.1038/s41598-017-16499-8.

Advanced glycation endproducts link inflammatory cues to upregulation of galectin-1 in diabetic retinopathy.

Author information

1
Laboratory of Ocular Cell Biology and Visual Science, Department of Ophthalmology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, 060-8638, Japan. kanda@med.hokudai.ac.jp.
2
Department of Ophthalmology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, 060-8638, Japan. kanda@med.hokudai.ac.jp.
3
Laboratory of Ocular Cell Biology and Visual Science, Department of Ophthalmology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, 060-8638, Japan.
4
Department of Ophthalmology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, 060-8638, Japan.
5
Laboratory of Ocular Cell Biology and Visual Science, Department of Ophthalmology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, 060-8638, Japan. ishidasu@med.hokudai.ac.jp.
6
Department of Ophthalmology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, 060-8638, Japan. ishidasu@med.hokudai.ac.jp.

Abstract

Diabetic retinopathy (DR) is an inflammatory and progressive vaso-occlusive disease resulting in angiogenesis. Galectin-1 is a hypoxia-induced angiogenic factor associated with cancer and proliferative DR. Here we reveal a significant upregulation of galectin-1 in eyes of DR patients along with progression of clinical stages beginning from the pre-ischemic, inflammatory stage with diabetic macular edema, but not in eyes with non-diabetic retinal vascular occlusions. As for its regulatory mechanism unrelated to hypoxia but selective to DR, in vitro galectin-1/LGALS1 expression was shown to increase after application to Müller glial cells with interleukin (IL)-1β, which was induced in monocyte-derived macrophages and microglial cells via toll-like receptor (TLR) 4 signaling stimulated by advanced glycation endproducts (AGE). In vivo inhibition of AGE generation with aminoguanidine, macrophage depletion with clodronate liposomes, and antibody-based blockade of Il-1β and Tlr4 attenuated diabetes-induced retinal Lgals1 expression in mice. Fibrovascular tissues from proliferative DR eyes were immunoreactive for AGE, TRL4 and IL-1β in macrophages, and IL-1β receptor-positive glial cells expressed galectin-1. Therefore, diabetes-induced retinal AGE accumulation was suggested to activate IL-1β-related inflammatory cues in macrophages followed by Müller cells, linking to galectin-1 upregulation in human DR with time. Our data highlight AGE-triggered inflammation as the DR-selective inducer of galectin-1.

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