The glucocorticoid receptor as a master regulator of Mueller cell gliosis in the diabetic retina

Abstract

Diabetic retinopathy (DR) is considered a primarily microvascular complication of diabetes. Muller glia cells are at the center of the retinal neurovascular unit and play a critical role in DR. We therefore investigated Muller cell-specific signaling pathways that are altered in DR to identify novel targets for gene therapy. Using a multi-omics approach on purified Muller 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 Muller cell gliosis in DR. 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 Muller 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. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=76 SRC="FIGDIR/small/556478v2_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@c7869forg.highwire.dtl.DTLVardef@1574edforg.highwire.dtl.DTLVardef@fb1329org.highwire.dtl.DTLVardef@1a6ee60_HPS_FORMAT_FIGEXP M_FIG C_FIG