The Role of Wnt/beta-Catenin Signaling and K-Cadherin in the Regulation of Intraocular Pressure

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dc.creatorWebber, Hannah C.
dc.creatorBermudez, Jaclyn Y.
dc.creatorMillar, J. Cameron
dc.creatorMao, Weiming
dc.creatorClark, Abbot F.
dc.creator.orcid0000-0003-3594-6560 (Clark, Abbot F.)
dc.date.accessioned2022-09-13T16:34:17Z
dc.date.available2022-09-13T16:34:17Z
dc.date.issued2018-03
dc.description.abstractPurpose: Wnt/beta-catenin signaling in the trabecular meshwork (TM) is required for maintaining normal intraocular pressure (IOP), although the mechanism(s) behind this are unknown. We hypothesize that Wnt/beta-catenin signaling regulates IOP via beta-catenin's effects on cadherin junctions. Methods: Nonglaucomatous primary human TM (NTM) cells were treated with or without 100 ng/ml Wnt3a, 1 mug/ml sFRP1, or both for 4 to 48 hours. Cells were immunostained for beta-catenin, total cadherins, or cadherin isoforms. Membrane proteins or whole-cell lysates were isolated for Western immunoblotting and probed for cadherin isoforms. RNA was extracted for cDNA synthesis and qPCR analysis of cadherin expression. Some NTM cells were cultured on electric plates for cell impedance assays. Ad5.CMV recombinant adenoviruses encoding K-cadherin, and/or sFRP1 were injected into eyes of 4- to 6-month-old female BALB/cJ mice (n = 8-10). Conscious IOPs were assessed for 35 days. Results: Upon Wnt3a treatment, total cadherin expression increased and beta-catenin accumulated at the TM cell membrane and on processes formed between TM cells. qPCR showed that Wnt3a significantly increased K-cadherin expression in NTM cells (P < 0.01, n = 3), and Western immunoblotting showed that Wnt3a increased K-cadherin in NTM cells, which was inhibited by the addition of sFRP1. Cell impedance assays showed that Wnt3a treatment increased transcellular resistance and anti-K-cadherin siRNA decreased transcellular resistance (P < 0.001, n = 4-6). Our in vivo study showed that K-cadherin significantly decreased sFRP1-induced ocular hypertension (P < 0.05, n = 6). Western immunoblotting also showed that K-cadherin alleviated sFRP1-induced beta-catenin decrease in mouse anterior segments. Conclusions: Our results suggest that cadherins play important roles in the regulation of TM homeostasis and IOP via the Wnt/beta-catenin pathway.
dc.description.sponsorshipSupported by National Institutes of Health Training Grant T32 AG 020494 (HCW, JWB) and 1R01EY026962-01A1 (WM).
dc.identifier.citationWebber, H. C., Bermudez, J. Y., Millar, J. C., Mao, W., & Clark, A. F. (2018). The Role of Wnt/β-Catenin Signaling and K-Cadherin in the Regulation of Intraocular Pressure. Investigative ophthalmology & visual science, 59(3), 1454-1466. https://doi.org/10.1167/iovs.17-21964
dc.identifier.issn1552-5783
dc.identifier.issue3
dc.identifier.urihttps://hdl.handle.net/20.500.12503/31730
dc.identifier.volume59
dc.publisherARVO Journals
dc.relation.urihttps://doi.org/10.1167/iovs.17-21964
dc.rights.holderCopyright 2018 The Authors
dc.rights.licenseAttribution 4.0 International (CC BY 4.0)
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.sourceInvestigative Ophthalmology & Visual Science
dc.subject.meshAnimals
dc.subject.meshBlotting, Western
dc.subject.meshCadherins / metabolism
dc.subject.meshCadherins / physiology
dc.subject.meshCell Membrane / metabolism
dc.subject.meshCells, Cultured
dc.subject.meshDisease Models, Animal
dc.subject.meshFemale
dc.subject.meshHumans
dc.subject.meshIntraocular Pressure / physiology
dc.subject.meshMice
dc.subject.meshMice, Inbred BALB C
dc.subject.meshProtein Isoforms / metabolism
dc.subject.meshSignal Transduction / physiology
dc.subject.meshTrabecular Meshwork / drug effects
dc.subject.meshTrabecular Meshwork / metabolism
dc.subject.meshWnt Signaling Pathway / physiology
dc.subject.meshWnt3A Protein / pharmacology
dc.subject.meshbeta Catenin / metabolism
dc.subject.meshbeta Catenin / physiology
dc.titleThe Role of Wnt/beta-Catenin Signaling and K-Cadherin in the Regulation of Intraocular Pressure
dc.typeArticle
dc.type.materialtext

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