Reducing Akt2 in retinal pigment epithelial cells causes a compensatory increase in Akt1 and attenuates diabetic retinopathy.
Animals
Cytokines
/ metabolism
Diabetes Mellitus, Experimental
/ complications
Diabetic Retinopathy
/ etiology
Epithelial Cells
/ metabolism
Glucose
/ metabolism
Glycogen Synthase Kinase 3 beta
/ genetics
Humans
Mice
NF-kappa B
/ metabolism
Proto-Oncogene Proteins c-akt
/ metabolism
Retinal Pigment Epithelium
/ metabolism
Retinal Pigments
/ metabolism
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
13 10 2022
13 10 2022
Historique:
received:
07
06
2021
accepted:
03
10
2022
entrez:
13
10
2022
pubmed:
14
10
2022
medline:
18
10
2022
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 36229454
doi: 10.1038/s41467-022-33773-0
pii: 10.1038/s41467-022-33773-0
pmc: PMC9561713
doi:
Substances chimiques
Cytokines
0
NF-kappa B
0
Retinal Pigments
0
AKT1 protein, human
EC 2.7.11.1
AKT2 protein, human
EC 2.7.11.1
Akt1 protein, mouse
EC 2.7.11.1
Akt2 protein, mouse
EC 2.7.11.1
Glycogen Synthase Kinase 3 beta
EC 2.7.11.1
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
Glucose
IY9XDZ35W2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
6045Subventions
Organisme : NIDDK NIH HHS
ID : P30 DK020572
Pays : United States
Organisme : NEI NIH HHS
ID : R01 EY029750
Pays : United States
Organisme : NEI NIH HHS
ID : T32 EY017271
Pays : United States
Informations de copyright
© 2022. The Author(s).
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