The Canonical Wnt Signaling Pathway Inhibits the Glucocorticoid Receptor Signaling Pathway in the Trabecular Meshwork

Chenna Kesavulu Sugali, Naga Pradeep Rayana, Jiannong Dai, Michael Peng, Sherri L. Harris, Hannah C. Webber, Shaohui Liu, Stephan G. Dixon, Priyanka H. Parekh, Elizabeth A. Martin, Louis B. Cantor, Ronald L. Fellman, David G. Godfrey, Michelle R. Butler, Matthew E. Emanuel, Davinder S. Grover, Oluwatosin U. Smith, Abbot F. Clark, Vijay Krishna Raghunathan, Weiming Mao

Research output: Contribution to journalArticlepeer-review

Abstract

Glucocorticoid-induced glaucoma is a secondary open-angle glaucoma. About 40% of the general population may develop elevated intraocular pressure on prolonged glucocorticoid treatment secondary to damages in the trabecular meshwork (TM), a tissue that regulates intraocular pressure. Therefore, identifying the key molecules responsible for glucocorticoid-induced ocular hypertension is crucial. In this study, Dickkopf-related protein 1 (Dkk1), a canonical Wnt signaling inhibitor, was found to be elevated in the aqueous humor and TM of glaucoma patients. At the signaling level, Dkk1 enhanced glucocorticoid receptor (GR) signaling, whereas Dkk1 knockdown or Wnt signaling activators decreased GR signaling in human TM cells as indicated by luciferase assays. Similarly, activation of the GR signaling inhibited Wnt signaling. At the protein level, glucocorticoid-induced extracellular matrix was inhibited by Wnt activation using Wnt activators or Dkk1 knockdown in primary human TM cells. In contrast, inhibition of canonical Wnt signaling by β-catenin knockdown increased glucocorticoid-induced extracellular matrix proteins. At the physiological level, adenovirus-mediated Wnt3a expression decreased glucocorticoid-induced ocular hypertension in mouse eyes. In summary, Wnt and GR signaling inhibit each other in the TM, and canonical Wnt signaling activators may prevent the adverse effect of glucocorticoids in the eye.

Original languageEnglish
Pages (from-to)1020-1035
Number of pages16
JournalAmerican Journal of Pathology
Volume191
Issue number6
DOIs
StatePublished - Jun 2021

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