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Weiming Mao, Naga Pradeep Rayana, Jinzi Wu, Amanda Roberts, Rafal Fudala; The role of Wnt signaling in TGFβ2-induced ocular hypertension. Invest. Ophthalmol. Vis. Sci. 2019;60(9):5133. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
In primary open angle glaucoma (POAG), the most important risk factor is elevated intraocular pressure (IOP). TGFβ2 and sFRP1, the ligand for the TGFβ signaling pathway and inhibitor for the Wnt signaling pathway, respectively, are elevated in POAG trabecular meshwork (TM). We previously showed that TGFβ and Wnt signaling pathways cross-inhibit each other in the TM. Here, we determined whether Wnt signaling is able to inhibit TGFβ2-induced ocular hypertension (OHT) and its potential mechanism.
Ad5-CMV-NULL/mWnt3a/mutant hTGFβ2 viruses were injected individually or as a mixture into the vitreous chamber of C57BL/6 mice. Mice IOP was measured under anesthesia using a TonoLab tonometer. Also, paired non-POAG human donor eyes were perfused with DMEM containing 100ng/ml Wnt3a and/or 5ng/ml TGFβ2. IOP was recorded using pressure transducers. Fluorescent protein tagged Smad4 and β-catenin were co-expressed in TM cells for Forster resonance energy transfer (FRET) study.
In female mouse eyes, viral transduction with Ad5-TGFβ2 induced OHT while Ad5-Wnt3a co-transduction decreased TGFβ2-induced OHT (n=5, p<0.05). In perfusion cultured human eyes, recombinant TGFβ2 also induced OHT in one eye while Wnt3a co-treatment either prevented or delayed OHT in the fellow eye (n=2). FRET studies indicated that Smad4 and β-catenin, the key mediators for the TGFβand Wnt pathways, may form a protein complex in TM cells.
Wnt signaling seems to antagonize TGFβ signaling in IOP regulation. More studies are required to further determine how the two pathways balance each other’s activities and maintain proper IOP.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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