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The role of Müller cell glucocorticoid signaling in diabetic retinopathy

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Abstract

Diabetic retinopathy (DR) is a sight-threatening complication associated with the highly prevalent diabetes disorder. Both the microvascular damage and neurodegeneration detected in the retina caused by chronic hyperglycemia have brought special attention to Müller cells, the major macroglia of the retina that are responsible for retinal homeostasis. Given the role of glucocorticoid signaling in anti-inflammatory responses and the almost exclusive expression of glucocorticoid receptors (GRs) in retinal Müller cells, administration of corticosteroid agonists as a potential treatment option has been widely studied. Although these approaches have been moderately efficacious in treating or de-escalating DR pathomechanisms, there are various side effects and gaps of knowledge with regard to introducing exogenous glucocorticoids to the diseased retina. In this paper, we provide a review of the literature concerning the available evidence for the role of Müller cell glucocorticoid signaling in DR and we discuss previously investigated approaches in modulating this system as possible treatment options. Furthermore, we propose a novel alternative to the available choices of treatment by using gene therapy as a tool to regulate the expression of GR in retinal Müller cells. Upregulating GR expression allows for induced glucocorticoid signaling with more enduring effects compared to injection of agonists. Hence, repetitive injections would no longer be required. Lastly, side effects of glucocorticoid therapy such as glucocorticoid resistance of GR following chronic exposure to excess ligands or agonists can be avoided.

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Acknowledgments

We thank Gabriele Jäger for her excellent technical assistance.

Funding

The project was funded by the University of British Columbia (UBC) to F.G. by providing financial support via the “UBC-Germany Scholarship” and the German Research Foundation (DFG) to A.G. (GR 4403/2-1) and to S.M.H. (HA6014/5-1).

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Authors and Affiliations

  1. Department of Physiological Genomics, Ludwig-Maximilians-Universität München, Großhaderner Str. 9, Martinsried, Germany

    Farhad Ghaseminejad, Lew Kaplan, Anna M. Pfaller & Antje Grosche

  2. Research Unit Protein Science, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Heidemannstr. 1, Neuherberg, Germany

    Stefanie M. Hauck

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  1. Farhad Ghaseminejad
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  2. Lew Kaplan
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Correspondence to Antje Grosche.

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Ghaseminejad, F., Kaplan, L., Pfaller, A.M. et al. The role of Müller cell glucocorticoid signaling in diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol 258, 221–230 (2020). https://doi.org/10.1007/s00417-019-04521-w

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