TY - JOUR
T1 - The Canonical Wnt Signaling Pathway Inhibits the Glucocorticoid Receptor Signaling Pathway in the Trabecular Meshwork
AU - Sugali, Chenna Kesavulu
AU - Rayana, Naga Pradeep
AU - Dai, Jiannong
AU - Peng, Michael
AU - Harris, Sherri L.
AU - Webber, Hannah C.
AU - Liu, Shaohui
AU - Dixon, Stephan G.
AU - Parekh, Priyanka H.
AU - Martin, Elizabeth A.
AU - Cantor, Louis B.
AU - Fellman, Ronald L.
AU - Godfrey, David G.
AU - Butler, Michelle R.
AU - Emanuel, Matthew E.
AU - Grover, Davinder S.
AU - Smith, Oluwatosin U.
AU - Clark, Abbot F.
AU - Raghunathan, Vijay Krishna
AU - Mao, Weiming
N1 - Funding Information:
Supported by the National Eye Institute ( NEI ) of the National Health Institute (NIH) under award number R01EY026962 (W.M.), Indiana University School of Medicine Showalter Scholarship (W.M.), BrightFocus Foundation G2017151 (W.M.), Cure Glaucoma Foundation (W.M.), the Indiana Clinical and Translational Sciences Institute funded, in part by award number UL1TR002529 from the NIH, National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award (W.M.), partially by NEI R01EY030967 (A.F.C.), and NEI R01EY026048 (V.K.R.).
Publisher Copyright:
© 2021 American Society for Investigative Pathology
PY - 2021/6
Y1 - 2021/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85106466609&partnerID=8YFLogxK
U2 - 10.1016/j.ajpath.2021.02.018
DO - 10.1016/j.ajpath.2021.02.018
M3 - Article
C2 - 33705750
AN - SCOPUS:85106466609
SN - 0002-9440
VL - 191
SP - 1020
EP - 1035
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 6
ER -