Reducing Akt2 in retinal pigment epithelial cells causes a compensatory increase in Akt1 and attenuates diabetic retinopathy.

Autor: Liu H; Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA., Stepicheva NA; Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA., Ghosh S; Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA., Shang P; Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.; Doheny Eye Institute, Pasadena, CA, USA., Chowdhury O; Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA., Daley RA; Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA., Yazdankhah M; Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.; Neural Stem Cell Institute, Rensselaer, NY, USA., Gupta U; Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA., Hose SL; Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA., Valapala M; School of Optometry, Indiana University, Bloomington, IN, USA., Fitting CS; Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA., Strizhakova A; Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA., Shan Y; Kellogg Eye Center, University of Michigan School of Medicine, Ann Arbor, MI, USA., Feenstra D; Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche, Ltd., Basel, Switzerland., Sahel JA; Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.; Institut de la Vision, INSERM, CNRS, Sorbonne Université, Paris, France., Jayagopal A; Opus Genetics, Durham, NC, USA., Handa JT; The Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD, USA., Zigler JS Jr; The Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD, USA., Fort PE; Kellogg Eye Center, University of Michigan School of Medicine, Ann Arbor, MI, USA., Sodhi A; The Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD, USA., Sinha D; Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Debasish@pitt.edu.; The Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. Debasish@pitt.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2022 Oct 13; Vol. 13 (1), pp. 6045. Date of Electronic Publication: 2022 Oct 13.
DOI: 10.1038/s41467-022-33773-0
Abstrakt: 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 GSK3β/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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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