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

Haitao Liu, Nadezda A. Stepicheva, Sayan Ghosh, Peng Shang, Olivia Chowdhury, Rachel A. Daley, Meysam Yazdankhah, Urvi Gupta, Stacey L. Hose, Mallika Valapala, Christopher Scott Fitting, Anastasia Strizhakova, Yang Shan, Derrick Feenstra, José-Alain Sahel, Ashwath Jayagopal, James T. Handa, J. Samuel Zigler, Patrice E. Fort, Akrit Sodhi and Debasish Sinha ()
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Haitao Liu: University of Pittsburgh School of Medicine
Nadezda A. Stepicheva: University of Pittsburgh School of Medicine
Sayan Ghosh: University of Pittsburgh School of Medicine
Peng Shang: University of Pittsburgh School of Medicine
Olivia Chowdhury: University of Pittsburgh School of Medicine
Rachel A. Daley: University of Pittsburgh School of Medicine
Meysam Yazdankhah: University of Pittsburgh School of Medicine
Urvi Gupta: University of Pittsburgh School of Medicine
Stacey L. Hose: University of Pittsburgh School of Medicine
Mallika Valapala: Indiana University
Christopher Scott Fitting: University of Pittsburgh School of Medicine
Anastasia Strizhakova: University of Pittsburgh School of Medicine
Yang Shan: University of Michigan School of Medicine
Derrick Feenstra: F. Hoffmann-La Roche, Ltd.
José-Alain Sahel: University of Pittsburgh School of Medicine
Ashwath Jayagopal: Opus Genetics
James T. Handa: The Johns Hopkins University School of Medicine
J. Samuel Zigler: The Johns Hopkins University School of Medicine
Patrice E. Fort: University of Michigan School of Medicine
Akrit Sodhi: The Johns Hopkins University School of Medicine
Debasish Sinha: University of Pittsburgh School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: 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 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.

Date: 2022
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33773-0

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DOI: 10.1038/s41467-022-33773-0

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