Weiming Mao PhD Indiana University School of Medicine, Ophthalmology
Co-authors: Chenna Kesavulu Sugali PhD Naga Pradeep Rayana MS
Glucocorticoids (GCs) cause GC-induced glaucoma (GIG) in a subpopulation of patients. With the introduction of sustained release intraocular GCs, ocular hypertension (OHT) and GIG are frequently observed in many patients. Our published data showed that the canonical Wnt pathway genes are involved in GC responsiveness using RNA sequencing, which suggests the role of Wnt signaling in GIG. In a mouse GIG model, we found that intravitreal injection of adenovirus expressing Wnt3a, a Wnt pathway activator inhibited dexamethasone (DEX)-induced OHT. At trabecular meshwork (TM) cell level, we found that activation of canonical Wnt signaling using Wnt3a inhibited glucocorticoid receptor (GR) signaling while inhibition of canonical Wnt signaling using sFRP1 enhanced GR signaling. Small molecule compounds that inhibit GSK3β inhibited DEX-induced ECM in the TM. Similar inhibition was observed by knocking down Dkk1, another Wnt pathway inhibitor using siRNA, and this inhibition was dose dependent. Co-immunoprecipitation using either GR antibody or β-catenin antibody showed that both GR and β-catenin could be pulled down from the nuclear fraction. We also found that HDAC1 and MeCP2 were pulled down together with GR and β-catenin. We hypothesize that the formation of a nuclear complex consisting of GR, β-catenin, HDAC1 and MeCP2 suppresses the expression of genes of the GR pathway that are involved in OHT. In summary, our studies suggest that activation of the Wnt pathway would be a promising approach to prevent or inhibit GC-induced OHT.