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Nat Commun ; 13(1): 6045, 2022 10 13.
Article in English | MEDLINE | ID: mdl-36229454

ABSTRACT

The retinal pigment epithelium (RPE) plays an important role in the development of diabetic retinopathy (DR), a leading cause of blindness worldwide. Here we set out to explore the role of Akt2 signaling-integral to both RPE homeostasis and glucose metabolism-to DR. Using human tissue and genetically manipulated mice (including RPE-specific conditional knockout (cKO) and knock-in (KI) mice), we investigate whether Akts in the RPE influences DR in models of diabetic eye disease. We found that Akt1 and Akt2 activities were reciprocally regulated in the RPE of DR donor tissue and diabetic mice. Akt2 cKO attenuated diabetes-induced retinal abnormalities through a compensatory upregulation of phospho-Akt1 leading to an inhibition of vascular injury, inflammatory cytokine release, and infiltration of immune cells mediated by the GSK3ß/NF-κB signaling pathway; overexpression of Akt2 has no effect. We propose that targeting Akt1 activity in the RPE may be a novel therapy for treating DR.


Subject(s)
Diabetes Mellitus, Experimental , Diabetic Retinopathy , Proto-Oncogene Proteins c-akt/metabolism , Animals , Cytokines/metabolism , Diabetes Mellitus, Experimental/complications , Diabetes Mellitus, Experimental/genetics , Diabetes Mellitus, Experimental/metabolism , Diabetic Retinopathy/etiology , Epithelial Cells/metabolism , Glucose/metabolism , Glycogen Synthase Kinase 3 beta/genetics , Glycogen Synthase Kinase 3 beta/metabolism , Humans , Mice , NF-kappa B/metabolism , Retinal Pigment Epithelium/metabolism , Retinal Pigments/metabolism
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