TY - JOUR
T1 - Reducing Akt2 in retinal pigment epithelial cells causes a compensatory increase in Akt1 and attenuates diabetic retinopathy
AU - Liu, Haitao
AU - Stepicheva, Nadezda A.
AU - Ghosh, Sayan
AU - Shang, Peng
AU - Chowdhury, Olivia
AU - Daley, Rachel A.
AU - Yazdankhah, Meysam
AU - Gupta, Urvi
AU - Hose, Stacey L.
AU - Valapala, Mallika
AU - Fitting, Christopher Scott
AU - Strizhakova, Anastasia
AU - Shan, Yang
AU - Feenstra, Derrick
AU - Sahel, José Alain
AU - Jayagopal, Ashwath
AU - Handa, James T.
AU - Zigler, J. Samuel
AU - Fort, Patrice E.
AU - Sodhi, Akrit
AU - Sinha, Debasish
N1 - Publisher Copyright: © 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85139970155
U2 - 10.1038/s41467-022-33773-0
DO - 10.1038/s41467-022-33773-0
M3 - Article
C2 - 36229454
SN - 2041-1723
VL - 13
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 6045
ER -