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

Author

Listed:
  • 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
    Doheny Eye Institute)

  • 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
    Neural Stem Cell Institute)

  • 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
    Sorbonne Université)

  • 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
    The Johns Hopkins University School of Medicine)

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.

Suggested Citation

  • 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 & An, 2022. "Reducing Akt2 in retinal pigment epithelial cells causes a compensatory increase in Akt1 and attenuates diabetic retinopathy," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33773-0
    DOI: 10.1038/s41467-022-33773-0
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    Cited by:

    1. Sayan Ghosh & Ruchi Sharma & Sridhar Bammidi & Victoria Koontz & Mihir Nemani & Meysam Yazdankhah & Katarzyna M. Kedziora & Donna Beer Stolz & Callen T. Wallace & Cheng Yu-Wei & Jonathan Franks & Devi, 2024. "The AKT2/SIRT5/TFEB pathway as a potential therapeutic target in non-neovascular AMD," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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