Highlights
- •Kdm6a is the epigenetic switch in microglia/macrophages and upregulated by high glucose challenge.
- •Loss of Kdm6a in microglia/macrophages ameliorated the retinal thickness decreasing, inflammation, and visual impairment.
- •Lcn2 is regulated by Kdm6a in microglia/macrophages and impact the glycolysis of photoreceptors.
- •Our study provides a valuable strategy to inhibit the progression of diabetic retinopathy by targeting the Kdm6a/Lcn2 axis.
Abstract
Diabetic retinopathy (DR) is one of the leading causes of severe visual impairment
worldwide. However, the role of adaptive immune inflammation driven by microglia/macrophages
in DR is not yet well elucidated. Kdm6a is a histone demethylase that removes the
trimethyl groups of histones H3K27 and plays important biological roles in activating
target genes. To elucidate the role of Kdm6a in microglia/macrophages in diabetic
retinas, we established diabetic animal models with conditional knockout mice to investigate
the impacts of Kdm6a deficiency. The RNA-seq analysis, mass spectrum examination,
immunohistochemistry and detection of enzyme activities were used to elucidate the
effect of Kdm6a deletion on gene transcription in microglia/macrophages. The expression
of Kdm6a was increased in the retinas of diabetic mice compared to the control group.
Loss of Kdm6a in microglia/macrophages ameliorated the diabetes-induced retinal thickness
decrease, inflammation, and visual impairment. Kdm6a in microglia/macrophages regulated
Lcn2 expression in a demethylase activity-dependent manner and inhibited glycolysis
progression in photoreceptor cells through Lcn2. These results suggest that Kdm6a
in microglia/macrophages aggravated diabetic retinopathy by promoting the expression
of Lcn2 and impairing glycolysis progression in photoreceptor cells.
Graphical abstract
Graphical Abstract
Abbreviations:
DR (diabetic retinopathy), Kdm6a (Histone lysine demethylase 6a), Lcn2 (Lipocalin-2), H3k27me3 (tri-methyl groups on histone 3 lysine 27), IRBP (interphotoreceptor retinoid-binding protein)Keywords
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Article info
Publication history
Published online: August 19, 2022
Accepted:
August 16,
2022
Received:
February 6,
2022
Identification
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