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Hyewon Chung, Kyu Hyung Park, Ae Jin Choi, Se Joon Woo, Jeehyun Yoon; Wnt Modulators in the Aqueous Humor are Associated with Severity of Outer Retinal Damage in Patients with Neovascular AMD. Invest. Ophthalmol. Vis. Sci. 2014;55(13):618.
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© ARVO (1962-2015); The Authors (2016-present)
The Wnt pathways have been linked to numerous cellular processes including angiogenesis and cellular survival. However, little is known regarding dysregulated Wnt pathways in AMD patients. Our previous proteomic study identified Wnt modulators, Wnt inhibitory factor 1 (WIF-1) and Dickkopf 3 (DKK-3) in the aqueous humor (AH) of AMD patients. We are attempting to verify the increase of these proteins and their clinical implications in AMD.
We measured WIF-1 and DKK-3 by immunoblotting and enzyme immunoassay (ELISA) in AH from 20 and 49 neovascular AMD patients, respectively. Prior to and two months after treatment with ranibizumab (pre and post) with matched controls, the association of levels in ELISA with SD-OCT parameters, including disruption length of the junction between inner and outer segments of the photoreceptor (IS/OS) were investigated. Primary rat retinal cells and ARPE-19 cells exposed to H2O2 along with their conditioned medium were examined for the expression of these proteins. Retinas and RPE from light-exposed mice were also analyzed.
Immunoblotting showed that WIF-1 and DKK-3 increased in 20 patients compared to controls. ELISA analysis demonstrated that WIF-1 (pre) and DKK-3 (pre) were elevated in 49 patients compared to controls (47.2 vs.25.0; 114.3 vs.93.0 ng/ml). High WIF-1 (pre) was associated with IS/OS (pre), IS/OS (post), and high WIF-1 (post) with multivariate analysis. Interestingly, WIF-1 (pre) is significantly different among patients with CNV, polypoidal choroidal vasculopathy (PCV), and retinal angiomatous proliferation (RAP) (44.6±22.5, 43.5±24.5, 79.3±17.8 ng/ml). A post-hoc multiple comparison test confirmed that WIF-1 (pre) in RAP patients was significantly high compared to CNV or PCV patients. WIF-1 was increased in retinal cells and culture medium exposed to H2O2 along with retinas of light-exposed mice, while DKK-3 was increased in both the retinas and RPE of these mice.
Increased WIF-1 and DKK-3 in the AH of AMD patients indicate that these proteins are significantly upregulated in AMD, possibly contributing to antagonize the upregulated Wnt signaling in AMD. In addition, shedded WIF-1 can be a new biomarker with potential for the prediction of the healthy or disease state of the retina.
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