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Rajesh Sasikumar, Shaika Shanbagh, Sushma Tejwani, Arkasubhra Ghosh; Differential Aquaporin Levels In Trabecular Meshwork Of Glaucoma Patients Are Regulated By Cross Talk Between Wnt And IFNβ Signaling. Invest. Ophthalmol. Vis. Sci. 201657(12):.
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© ARVO (1962-2015); The Authors (2016-present)
Aquaporins (AQP) are membrane water channels that maintain hydrostatic, osmotic and ionic balance. The functions of AQP0 and AQP6 have not been examined in glaucoma patients. Altered Wnt signaling has been linked to glaucoma but human data is sparse. IFNβ is an important immune-modulatory cytokine that is in turn regulated by GSK3β, an aspect not investigated in glaucoma. This study investigated the regulation of AQPs in the context of Wnt regulation and cross talk with inflammation.
All samples were collected after written, informed consent and approval of the Institutional Ethics Committee. Trabecular meshwork (TM) tissue from glaucoma filtration surgery patients (n=40) and cadaveric controls (n=20) were used for expression analysis of Wnt target gene Axin2, IFNβ, IL6, AQP0 AQP6 and AQP9. Human Trabecular Meshwork (HTM) cells, cultured in DMEM with 10% FBS and 1% PSA were treated with Wnt activator (AZD2858; GSK3β inhibitor) or inhibitor (XAV939; β-catenin inhibitor) and analysed after 24 hours for expression of the same genes.
In patient TM samples, we observed a distinct loss of AQP0 (p=0.009), AQP9 (p=0.002) and increase in AQP6 and IL6 associated with increased Axin2 (p=0.04) and reduced IFNβ (0.01) when compared to controls. Activation of Wnt pathway (using chemical activator AZD2858) in HTM culture recapitulated the patient data demonstrating a reduction in AQP0, AQP9 and IFNβ expression, but significantly induced Axin2, AQP6 and IL6. Wnt inhibition reversed the same observations.
This is the first study that suggests a role for AQP6, AQP0 and AQP9 in glaucoma patient trabecular meshwork. Upregulated Axin2 levels in both patients and HTM cells correlated with decreased IFNβ that may be mediated through inhibition of GSK3β. The data uncovers cross talk between Wnt and IFNβ as a possible mechanism that regulates expression of critical AQPs 0, 6 and 9 leading to loss of hydrostatic and osmotic balance in glaucoma. Our observations suggest that Wnt inhibitors may be explored as a possible treatment modality for glaucoma.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
Aqp-9 expression in Trabecular meshwork & HTM cells
Aqp-0 expression in Trabecular meshwork & HTM cells
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