Pfaller, A.M.* ; Kaplan, L.* ; Moreira Carido Pereira, M. ; Grassmann, F.* ; Díaz-Lezama, N.* ; Ghaseminejad, F.* ; Wunderlich, K.A.* ; Glänzer, S.* ; Bludau, O.* ; Pannicke, T.* ; Weber, B.H.F.* ; Koch, S.F.* ; Bonev, B. ; Hauck, S.M. ; Grosche, A.*
The glucocorticoid receptor as a master regulator of the Müller cell response to diabetic conditions in mice.
J. Neuroinflamm. 21:33 (2024)
Diabetic retinopathy (DR) is considered a primarily microvascular complication of diabetes. Müller glia cells are at the centre of the retinal neurovascular unit and play a critical role in DR. We therefore investigated Müller cell-specific signalling pathways that are altered in DR to identify novel targets for gene therapy. Using a multi-omics approach on purified Müller cells from diabetic db/db mice, we found the mRNA and protein expression of the glucocorticoid receptor (GR) to be significantly decreased, while its target gene cluster was down-regulated. Further, oPOSSUM TF analysis and ATAC- sequencing identified the GR as a master regulator of Müller cell response to diabetic conditions. Cortisol not only increased GR phosphorylation. It also induced changes in the expression of known GR target genes in retinal explants. Finally, retinal functionality was improved by AAV-mediated overexpression of GR in Müller cells. Our study demonstrates an important role of the glial GR in DR and implies that therapeutic approaches targeting this signalling pathway should be aimed at increasing GR expression rather than the addition of more ligand.
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Publication type
Article: Journal article
Document type
Scientific Article
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Editors
Keywords
Diabetic Retinopathy ; Glucocorticoid Receptor Signalling ; Müller Glia ; Proteomic Analysis ; Mrna expression Profiling; Endothelial Growth-factor; Muller Glial-cells; Retinal Barrier Breakdown; Membrane Conductance; Factor Expression; Oxidative Stress; Mouse Models; Db/db Mouse; Activation; Dysfunction
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Language
english
Publication Year
2024
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0
HGF-reported in Year
2024
ISSN (print) / ISBN
1742-2094
e-ISSN
1742-2094
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Volume: 21,
Issue: 1,
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Article Number: 33
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BioMed Central
Publishing Place
London
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Reviewing status
Peer reviewed
POF-Topic(s)
30204 - Cell Programming and Repair
30203 - Molecular Targets and Therapies
Research field(s)
Pioneer Campus
Enabling and Novel Technologies
PSP Element(s)
G-510004-001
G-505700-001
A-630700-001
Grants
Ministry of Science, Research and Technology of Mexico City Government (SECITI)
UBC-German Scholarship
ProRetina Foundation Germany
Bayer GOAP Research Award 2016
German Research Foundation
Copyright
Erfassungsdatum
2024-01-29